Involvement of kinases in memory consolidation of inhibitory avoidance training

Ivan Montiel; Paola C. Bello-Medina; Roberto A. Prado-Alcalá; Gina L. Quirarte; Luis A. Verdín-Ruvalcaba; Tzitzi A. Marín-Juárez; Andrea C. Medina

doi:10.1515/revneuro-2024-0093

Article Open Access

Involvement of kinases in memory consolidation of inhibitory avoidance training

Ivan Montiel , Paola C. Bello-Medina , Roberto A. Prado-Alcalá , Gina L. Quirarte , Luis A. Verdín-Ruvalcaba , Tzitzi A. Marín-Juárez and Andrea C. Medina

Published/Copyright: September 27, 2024

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From the journal Reviews in the Neurosciences Volume 36 Issue 2

Abstract

The inhibitory avoidance (IA) task is a paradigm widely used to investigate the molecular and cellular mechanisms involved in the formation of long-term memory of aversive experiences. In this review, we discuss studies on different brain structures in rats associated with memory consolidation, such as the hippocampus, striatum, and amygdala, as well as some cortical areas, including the insular, cingulate, entorhinal, parietal and prefrontal cortex. These studies have shown that IA training triggers the release of neurotransmitters, hormones, growth factors, etc., that activate intracellular signaling pathways related to protein kinases, which induce intracellular non-genomic changes or transcriptional mechanisms in the nucleus, leading to the synthesis of proteins. We have summarized the temporal dynamics and crosstalk among protein kinase A, protein kinase C, mitogen activated protein kinase, extracellular-signal-regulated kinase, and Ca²⁺/calmodulin-dependent protein kinase II described in the hippocampus. Protein kinase activity has been associated with structural changes and synaptic strengthening, resulting in memory storage. However, little is known about the molecular mechanisms involved in intense IA training, which protects memory from typical amnestic treatments, such as protein synthesis inhibitors, and induces increased spinogenesis, suggesting an unexplored mechanism independent of the genomic pathway. This highly emotional experience causes an extinction-resistant memory, as has been observed in some pathological states such as post-traumatic stress disorder. We propose that the changes in spinogenesis observed after intense IA training could be generated by protein kinases via non-genomic pathways.

Keywords: aversive memory; intense training; long-term memory; non-genomic mechanisms; protein kinases

1 Introduction

To survive, organisms must be able to store and recall information about the stimuli from their environment, especially those that represent danger or discomfort (such as fear or pain). These types of stimuli are called aversive, and organisms perform appropriate responses to avoid them (Izquierdo et al. 2016; LeDoux et al. 2017; Netto and Izquierdo 1985; Randall and Riccio 1969).

Avoidance responses have been studied in invertebrates (Bardou et al. 2010; Denti et al. 1988; Kim et al. 2010; Marchal et al. 2019; Peckmezian and Taylor 2015; Shomrat et al. 2008) and vertebrates (Blank et al. 2009; Burchuladze et al. 1990; Grignolo et al. 1981; Macphail 1968; Wodinsky et al. 1962; Zhao et al. 1999). Rodents (mice and rats) have been the model of choice used to explore the neurobiological basis of memory of aversive experiences (Bammer et al. 1977; Blozovski and Cudennec 1980; Doty and Johnston 1966; Izquierdo et al. 2016; Janak et al. 1994; LeDoux et al. 2017; McLaughlin et al. 1975; Sprott 1972; Zhang et al. 2011). One commonly used paradigm is the inhibitory avoidance task (IA).

There are different types of IA. The most common are the one-trial step-down and one-trial step-through tasks (Bures et al. 2016; Carew 1970; Ögren and Stiedl 2010); the most notable differences between them are the way the animal must execute the avoidance response and the characteristics of the conditioning chamber. Originally introduced by Jarvik and Kopp in 1967 as a learning paradigm for mice, the step-through version has found widespread use in rat research. In this modality, the conditioning chamber has two compartments separated by a guillotine door. One of the compartments is illuminated and has a floor made of stainless-steel bars. This context is considered “safe” because it is not associated with an electric foot shock. The other compartment is dark and is considered a “punishment” context because the animal receives a foot shock in it. The trial begins when the animal is placed in the safe compartment. After a brief time of free exploration, the guillotine door is opened, and the animal can cross into the punishment compartment. When the animal fully enters the punishment compartment, the guillotine door is closed, and an electric foot shock is administered. The duration of the aversive stimulation is short, and the animal is removed from the chamber at the end of the foot shock, thus ending the trial. Evaluating memory consolidation and retrieval entails placing the animal again in the safe compartment and measuring the time it takes to enter the punishment compartment (Branchi and Ricceri 2013; Carew 1970; Jarvik and Kopp 1967; Olton 1973; Sara et al. 1975). Thus, the association of the punishment compartment and the foot shock leads to an avoidance response, wherein the subject inhibits its motor response to return to the punishment compartment, thus avoiding the electric shock (Ögren and Stiedl 2010; Randall and Riccio 1969). In the step-down version, the animal is placed onto a small platform, adjacent to one of the walls of the conditioning chamber; once it steps down it receives an electric foot shock. Memory consolidation and recall are measured by placing the animal on the platform a second time and the time it takes to step down again is measured (Bures et al. 2016; Carew 1970; Jarvik and Essman 1960; Netto and Izquierdo 1985).

In comparison to multiple training tasks, the IA paradigm requires only a single training session, which enables the researcher to discriminate between the different memory stages (acquisition, consolidation, and retrieval) (Barros et al. 2004b; Eagle et al. 2016; Lorenzini et al. 1996, 1997]; Shahidi et al. 2008) allowing for the study of those stages at different levels (molecular, cellular, physiological, and behavioral) (Bekinschtein et al. 2010; González-Franco et al. 2017, 2019]; Igaz et al. 2004a,b; Izquierdo et al. 1995, 2002], 2006]; López-Hidalgo et al. 2012; Ruiz-López et al. 2021).

This behavioral paradigm provides a straightforward methodological approach to identify how different brain structures are involved in processing the various components of the task (Huff et al. 2016; Malin and McGaugh 2006; Malin et al. 2007; Medina et al. 2007; Roozendaal et al. 2009; Wahlstrom et al. 2018). The foot shock activates the emotional component, the distinctions between safe and punishment compartments trigger the spatial component, and the relationship between step-down/through behavior and the foot shock consequence integrates the motor and associative components.

Numerous experiments have aimed at identifying the brain structures involved in IA memory consolidation. These studies have employed various methodological approaches, including classical techniques such as permanent or temporary lesions and pharmacological approaches utilizing channel blockers or neurotransmitter agonists or antagonists, in different cerebral structures such as the hippocampus (Afshar et al. 2023; Bianchin et al. 1994; Bonini et al. 2003; Izquierdo and Medina 1997; Izquierdo et al. 1992, 1997]; Lorenzini et al. 1996, 1997]; Rossato et al. 2004; Simonyi et al. 2007), amygdala (Bianchin et al. 1994, 2000]; Bonini et al. 2003; Gallagher et al. 1977; Izquierdo and Medina 1997; Izquierdo et al. 1992, 1997]; Jafari-Sabet 2006; Morena et al. 2021; Rossato et al. 2004; Salado-Castillo et al. 2011), striatum (Giordano and Prado-Alcalá 1986; Martínez-Degollado et al. 2024; Pérez-Ruiz and Prado-Alcalá 1989; Prado-Alcalá et al. 2003; Salado-Castillo et al. 1996, 2011]; Sánchez-Resendis et al. 2012), medial septum (Izquierdo et al. 1992), substantia nigra (Salado-Castillo et al. 2011), entorhinal cortex (Bonini et al. 2003; Izquierdo et al. 1997; Rossato et al. 2004), insular cortex (Bermudez-Rattoni et al. 1991; Miranda and Bermudez-Rattoni 2007), parietal cortex (Bonini et al. 2003; Izquierdo et al. 1997; Rossato et al. 2004), and prefrontal cortex (Gonzalez et al. 2013; Torres-García et al. 2017).

We have chosen to narrow the scope of this review to studies conducted exclusively in rats. This approach was taken because of the scarcity of studies comparing neurobiological differences in memory consolidation of IA between rats and mice. Regarding these two species, differences in the activation levels of extracellular-signal-regulated kinase (ERK) have been reported (Han and Kim 2003), and it has been proposed that some physiological mechanisms involved in memory consolidation differ (Prado-Alcalá et al. 2020).

At a molecular level, an IA learning experience produces neuronal activation that induces the release of neurotransmitters, hormones, growth factors, etc., which, once coupled to their receptors, promote the intracellular increase of second messengers such as Ca²⁺, 3′,5′-cyclic adenosine monophosphate (cAMP), 3′,5′-cyclic guanosine monophosphate (cGMP), etc. (Bernabeu et al. 1996; Micheau and Riedel 1999; Shobe 2002). These second messengers will trigger a series of complex signaling cascades in brain cells (Asok et al. 2019; Kandel 2001; Micheau and Riedel 1999), as will be described later.

The molecular changes associated with IA memory formation, as assessed by a retention test performed one or two days after training, have been the focus of experimental inquiry in the recent past. Evidence has contributed to understanding the role of these signaling cascades through the evaluation of changes in protein levels related to synaptic plasticity and their potential role in IA memory consolidation in rats. Research has focused on c-Fos (Cammarota et al. 2000; Katche et al. 2010; Ruiz-López et al. 2021), Arc (González-Franco et al. 2017; Holloway and McIntyre 2011; Holloway-Erickson et al. 2012; McIntyre et al. 2005; McReynolds et al. 2010; 2014]), phosphorylated glucocorticoid receptor (pGR) (González-Franco et al. 2023), membrane receptors such as insulin-like growth factor II (IGF2) (Lee et al. 2015), tyrosine kinase receptor B (TrKB) (Blank et al. 2016; Chen et al. 2012), other proteins involved in signal transduction such as syntaxin 1a (STX1A), structure-specific structure recognition protein 1 (SSRP1) (Igaz et al. 2004a), gaseous messengers such as nitric oxide (Guerra et al. 2006; Tan 2007; Zinn et al. 2009), and carbon monoxide (CO) (Bernabeu et al. 1995b).

Protein kinases are enzymes that regulate the activity of proteins through phosphorylation of specific amino acids by adenosine triphosphate (ATP), making way for intracellular proteins that modify the properties and density of channels and membrane receptors (Izquierdo and Medina 1997; Shobe 2002), regulating gene expression and protein synthesis, leading to structural changes, and strengthening of synapses as well as synaptogenesis (Giese and Mizuno 2013; Van der Zee 2015).

Among the largest gene families in eukaryotes are the protein kinases, which have been divided into nine broad groups, 134 families, and 196 subfamilies. The classification of protein kinases is based on the evolutionary relationships determined by sequence analysis of their catalytic domains (Manning et al. 2002). A small subset of these kinases is involved in memory consolidation regulating the activity of other proteins through phosphorylating specific loci in other proteins (Giese and Mizuno 2013). This occurs as a consequence of activation membrane receptors, which in turn triggers the activation of different kinases such as Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), protein kinase C (PKC), protein kinase A (PKA) and mitogen-activated protein kinase (MAPK). The activation of these proteins induces parallel signaling cascades which are important in the process of memory (Izquierdo and Medina 1997; Izquierdo et al. 2006; Kandel 2001; Shobe 2002).

In this review, we describe and discuss the alterations in protein kinases associated with memory consolidation in the IA task. Furthermore, we explore how these protein kinases may converge to facilitate the structural and functional changes that are essential for long-term storage of this type of memory in rats.

2 Role of protein kinases in IA memory consolidation

2.1 PKA

PKA is a 3′-5′-cyclic adenosine monophosphate (cAMP)-dependent kinase. Structurally, it is composed of two catalytic subunits (PKAc) and two regulatory subunits (PKAr). When cAMP binds the PKAr subunits, the PKAc subunits are released and interact with downstream effectors (Morrison 2021; Sadeghian et al. 2022). The phosphorylation of PKA is crucial for the activation of the cAMP responsive element binding protein (CREB), a transcription factor involved in memory processes (Asok et al. 2019; Taubenfeld et al. 2001).

The cAMP/PKA/pCREB pathway has been studied in different brain structures to understand its participation in the IA task. Among those structures are the CA1 region of the hippocampus (Barros et al. 2004a; Bernabeu et al. 1997a,b; Bevilaqua et al. 1997; Izquierdo et al. 2000; Quevedo et al. 2004, 2005]; Taubenfeld et al. 2001; Vianna et al. 1999, 2000b, 2001]), amygdala (Ardenghi et al. 1997; Bevilaqua et al. 1997), entorhinal cortex (Ardenghi et al. 1997; Izquierdo et al. 2000; Pereira et al. 2001; Vianna et al. 2001), parietal cortex (Ardenghi et al. 1997; Pereira et al. 2001), and posterior cingulate cortex (Pereira et al. 2001; Souza et al. 2002).

In the CA1 region of the hippocampus, it has been observed that cAMP levels increase in response to training in the IA. Using a radioimmunoassay technique, Bernabeu et al. (1996) found that this increase occurs at 30 min after training, although it is higher after 3 h (Table 1). Additionally, cAMP levels remain high up to 6 h post-training (Bernabeu et al. 1997a,b) (Table 1), which has led to the conclusion that cAMP has a stronger relationship to late mechanisms of consolidation than to early ones. Quevedo et al. (2005) demonstrated that infusion of a PKA inhibitor (Rp-cAMP) altered memory in rats when administered into the hippocampus 15 min before, and 0 or 3 h after the training session, but not at 1.5 h post-training, showing two temporal windows of its activity related to memory formation.

Table 1:

Percentage of change relative to control values of protein kinase levels detected in the hippocampus of rats trained in the IA task at different times after training. * ≤ 50 %; ** 51–100 %; *** 101–150 %; **** 151–200 %; ***** 201–250 %; ****** 251–300 %.

Time Kinase	0 h	0.5 h	2 h	3 h	6 h	18 h	24 h	References
PKA		*		*				Bernabeu et al. (1996)
				****	***			Bernabeu et al. (1997a, b)
		*						Cammarota et al. (2000)
	****			*****				Vianna et al. (2000b)
	***			******				Pereira et al. (2001)
PKC	*	**	*					Bernabeu et al. (1995a)
		*						Cammarota et al. (1997)
	**	**	**					Paratcha et al. (2000)
MAPK	*							Alonso et al. (2003)
MAPK			**					Cammarota et al. (2000)
ERK			**					Cammarota et al. (2000)
	**							Alonso et al. (2002c)
							*	Igaz et al. (2004a)
		*		*				Cammarota et al. (2008)
							***	Bekinschtein et al. (2010)
CaMKII	**	*	*					Cammarota et al. (1998)
	**	*						Cammarota et al. (2004)
							*	Igaz et al. (2004a)
		*						Cammarota et al. (2008)
						***	****	Bekinschtein et al. (2010)

Moreover, it has been shown that adenylate cyclase activators or dopamine receptor (D1/D5) agonists have a memory-facilitating effect when administered into the hippocampus at 3 or 6 h post-training; this effect was blocked by dopamine antagonists or adenylate cyclase inhibitors, supporting the notion of cAMP involvement in the late phases of long-term memory formation (Bernabeu et al. 1997a). Bernabeu et al. (1997a) found that PKA activity in the hippocampus was significantly higher at 0, 3, and 6 h after IA training, based on biochemical assays (Table 1), while the levels of phosphorylated CREB (pCREB) were elevated, as shown by immunocytochemistry, and they found that the administration at 0, 3, or 6 h of KT5720, a specific inhibitor of the catalytic subunit of PKA, as well as D1/D5 receptor antagonists, produced amnesia, confirming the participation of this pathway in the consolidation process. Furini et al. (2014) reinforced these findings by administering specific antagonists of each of the D1 and D5 receptors in the hippocampus and reversing the amnestic effect with a PKA activator (8-Br-cAMP). Overall, these results suggest that the PKA/D1/D5 pathway in CA1 has a major role in memory formation (Bernabeu et al. 1997a,b; Furini et al. 2014) (Figure 1). Bernabeu et al. (1997b) showed that there is involvement of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the PKA/D1/D5 pathway close to training, as measured by immunoblot.

Figure 1:

Integrative schematic drawing illustrating the hippocampal signaling pathways of PKA, PKC, MAPK, ERK and CaMKII during memory consolidation of IA in rats. The black arrows indicate the sequence of events on the pathways and the green arrows indicate protein increase expression.

Based on drug administration studies, Bevilaqua et al. (1997) have proposed that the cAMP/PKA pathway in the hippocampus, but not the amygdala, is involved in memory consolidation through the regulation of D1, β-adrenergic, and 5-HT 1A receptors (Figure 1). It has been stated that this mechanism has a temporal window ranging from 3 to 6 h after training in the hippocampus. In addition, Vianna et al. (2000b) observed increases in PKA activity in CA1 region at 5 and 180 min after IA training, according to biochemical assay. The interruption of activity of PKA, with an inhibitor of the regulatory subunit of PKA (Rp-cAMPS), immediately after training in the entorhinal cortex caused amnesia (Vianna et al. 2001).

Furthermore, it has been demonstrated that administering anandamide, an agonist of cannabinoid receptors, in the CA1 region of the hippocampus before training induces amnesia in IA-trained rats. However, administration immediately after training of Sp-cAMPs, a stimulant of the regulatory subunit of PKA, reverses this effect, highlighting the interaction between PKA and endocannabinoid receptors in the process of memory formation (Barros et al. 2004a).

Other receptors in the hippocampus involved in memory consolidation of IA include the gastrin-releasing peptide-preferring receptor (GRPR). Pharmacological activation, immediately after training, of these receptors leads to memory facilitation, and this effect can be reversed by blockers of PKA (Rp-cAMP), PKC (Gö 7874), and MAPK activity (PD098059), administered before training (Roesler et al. 2006). Additionally, it has been demonstrated that coadministration of D1/D5 receptor and GRPR agonists potentiate memory facilitation, and this effect is blocked by a PKA inhibitor (Roesler et al. 2006). Furthermore, with the use of immunoblotting, it has been reported that the infusion of a PKA activator (8-Br-cAMP) during three consecutive days increases hippocampal neural cell adhesion molecules in trained rats, which are essential for synaptic plasticity related to memory formation (Razmi et al. 2014).

Ardenghi et al. (1997) evaluated the cAMP/PKA-dependent mechanisms in memory consolidation in the parietal cortex, entorhinal cortex, and amygdala. When given into the posterior parietal cortex and entorhinal cortex 0, 3, or 6, but not 9 h, after training, KT5790 (PKA inhibitor) produced amnesia. In addition, the administration of an adenylyl cyclase activator, a dopamine D receptor agonist or norepinephrine in the entorhinal cortex 0, 3, or 6 h post-training produced memory facilitation. The same effect was observed when these treatments were administered 3 or 6 h post-training in the parietal cortex. Also, norepinephrine administered into the amygdala immediately after training produced memory facilitation. These data suggest a role of cAMP/PKA-dependent mechanisms in memory formation in the entorhinal and parietal cortex, but not the amygdala, from 0 to 6 h after training.

Moreover, it has been demonstrated that the pharmacological activation of the glucocorticoid receptor (GR) in the basolateral amygdala (BLA) immediately after training induces memory facilitation. This effect was blocked by administering a β-adrenoreceptor antagonist (atenolol) as well as by a PKA inhibitor (Rp-cAMP) before training, confirming the involvement of adrenergic receptors in the cAMP/PKA signaling pathway and suggesting that the glucocorticoid system is also involved in the memory formation (Roozendaal et al. 2002).

Enzyme assays demonstrate two distinct peaks of PKA activity in the hippocampus following IA training: the first immediately after training and the second one 3 h later. Immunohistochemical analysis reveals similar peak activity of pCREB 30 min after training (Morris and Gold 2012) or 3–6 h later (Bernabeu et al. 1997a,b) (Table 1). Administration of KT5720, an inhibitor of PKA, at either of these two time points correlates with memory impairments. Conversely, administration of the agonists 8-Br-cAMP and forskolin at these times produces the opposite effect (Bernabeu et al. 1997a). None of these treatments affects long-term memory if they are administered 22, 45, or 90 min after training (Vianna et al. 1999).

Similar effects have been reported in the entorhinal cortex, where PKA activity was evaluated by measuring the incorporation of radiolabeled (ϒ-32P)ATP and the kemptide peptide, a selective substrate for PKA (Pereira et al. 2001). These authors reported an increase in PKA activity in the hippocampus immediately after training and 3 h later, while in the entorhinal cortex this increase occurs 3 h post-training. They also reported no changes in the PKA activity in the parietal and cingulate cortices (Pereira et al. 2001); however, administration of antagonists into these structures produces a deficit of memory (Souza et al. 2002), suggesting that parietal and cingulate cortices would simply require basal levels of PKA activity rather than an increase for mediating memory consolidation (Pereira et al. 2001).

2.2 PKC

PKC, a kinase family consisting of 12 different isoforms (Callender and Newton 2017; Newton 2018; Steinberg 2008), has been linked to memory processes (Izquierdo and Medina 1997; Izquierdo et al. 2000, 2006]; Serrano et al. 2008; Shobe 2002). The role of the classical (α, βI, βII, and γ) and novel (δ, ε, θ, and η) PKC isoforms has been demonstrated through the administration of antagonists which produce impairments in memory formation (Izquierdo et al. 2000, 2006]). By the same token, Jerusalinsky et al. (1994) reported an amnesic effect when non-selective PKC inhibitors (staurosporine and CGP 41231) were administered in CA1 at different times (0, 30, or 120 min) after training.

The involvement of PKC in the amygdala has also been investigated. Walker and Gold (1994) administered PMXB (PKC antagonist) and NPC 15437 (a general blocker of the classical PKC isoforms) immediately after training and observed impaired long-term memory when measured 48 h later.

Other investigators have studied the effects of PKC activation, which is related to the activity of acetylcholine and proteins involved in synaptic plasticity in cortical areas. For instance, Van der Zee et al. (1994) used immunofluorescent experiments to evaluate changes in PKCγ, muscarinic acetylcholine receptors, and microtubule-associated protein 2 (MAP-2) in cortical areas, increasing dendritic plasticity levels in neurons of layers 2, 3, and 5. Their findings revealed an elevation of these molecules 2 h after IA training.

Autoradiography experiments revealed an increase in [3H] phorbol-12,13 dibutyrate ([3H] PDBu) (a marker for PKC) was found in CA1 and CA2 regions of the dorsal hippocampus at 0, 30, and 120 min after training (Bernabeu et al. 1995a) (Table 1). Additionally, it has been reported that IA consolidation is linked to a rapid and specific elevation of B50/growth-associated protein 43 (GAP43) levels and PKC phosphorylation in dorsal hippocampal membrane synaptosomes at 30 min after training as determined by Western blot and in vitro phosphorylation assays, respectively (Cammarota et al. 1997) (Figure 1 and Table 1). These findings suggest the involvement of pre- and post-synaptic hippocampal glutamatergic neurons that could be related to the phosphorylation of B50 and GAP43 previously found in the dorsal hippocampus (Paratcha et al. 2000).

Vianna et al. (2000a) administered Gö 7874 (antagonist of PKC) and Go 6976 (inhibitor of PKC α, βI, and βII) in the CA1 of the dorsal hippocampus; they found an impairment in long-term memory when these drugs were delivered 10 min before, or 50, or 110 min after training. Bonini et al. (2005) reported that PKC isoforms have different temporal dynamics depending on the brain region studied, i.e., PKC activity (α, βI, and βII) in the BLA plays a relevant role in IA memory consolidation close to the time of training, whereas in the posterior parietal cortex, PKC α, βI, and βII, among other isoforms, become engaged three or more hours after training. These results suggest that PKC isoforms exhibit different temporal dynamics depending on the specific brain region evaluated, probably due to the different downstream targets they interact.

Administration of spermidine, an endogenous aliphatic amine that modulates N-methyl-d-aspartate (NMDA) receptor activity in the hippocampus, produced memory facilitation through phosphorylation of PKA/CREB (Guerra et al. 2011, 2012]) and PKC (Guerra et al. 2012). Furthermore, Guerra et al. (2012) showed that disruption of PKC by administration of GF 109203X (antagonist of classical and novel PKC isoforms) together with spermidine immediately after the IA task abolished the facilitation effect of spermidine. Therefore, the authors proposed that memory facilitation induced by spermidine administration in the hippocampus requires the interaction between of PKC and PKA/CREB, showing that there is a sequential activation of the PKC and PKA/CREB pathways (Guerra et al. 2012). More recent findings by Dahleh et al. (2024), using western immunoblotting, reported that spermidine induces an increase in phosphorylated CaMKIIα, PKC, and phosphorylated PKA in the hippocampus of IA task-trained rats at 15-, 30-, and 180-min post-treatment, respectively. Inactivation of CaMKIIα blocked the memory-facilitating action by reducing phosphorylated CaMKIIα and PKA. The authors proposed that activation of CaMKIIα and PKA facilitates CREB phosphorylation, whereas PKC could participate as a parallel mechanism, directly activating PKA and, subsequently, CREB, thus giving way to memory consolidation.

Furini et al. (2014) demonstrated that pharmacological activation of D1 and D5 receptors in the hippocampus is necessary for memory formation. They further established an interaction between these receptors and PKC. Their findings revealed that administration of D1 and D5 receptor antagonists in the hippocampus induces amnesia in rats trained in IA, and this amnesic effect is reversed with the administration of a PKC activator before training (PMA, 12-O-Tetradecanoylphorbol 13-acetate; 4β,9α,12β,13α,20-Pentahydroxytiglia-1,6-dien-3-one 12-tetradecanoate 13-acetate).

2.3 MAPK and ERK

Multicellular organisms have three subfamilies of MAPKs, namely c-Jun N-terminal kinases (JNK), p38-MAPKs, and extracellular signal-regulated protein kinases (ERK) (Johnson and Lapadat 2002) which regulate a wide variety of cellular processes, such as proliferation, differentiation, development, and apoptosis (Garrington and Johnson 1999; Roux and Blenis 2004; Zhang and Liu 2002). JNKs bind to the c-Jun protein and phosphorylate it, enhancing its transcriptional activity. c-Jun is a multifaceted transcriptional component that oversees gene expression related to cytokines, responses to cellular stress, and growth factors modulated by JNK’s activity (Johnson and Lapadat 2002).

There are four types of p38-MAPK: α, β, γ, and δ (Lee et al. 1994). They play a crucial role in the immune system and regulate the expression of numerous inflammatory cytokines by activating immune cells. The involvement of MAPK kinases in IA memory has also been reported. In a study by Walz et al. (1999a), they administered a MAPK inhibitor (PD098059) in CA1 or the entorhinal cortex; the treatment impaired memory when the inhibitor was administered immediately or 180 min after training. Similar effects were found when the inhibitor was administered in the amygdala (Walz et al. 2000); also, MAPK activity near the time of training in the parietal (Walz et al. 1999b, 2000]) and entorhinal cortex (Vianna et al. 2001; Walz et al. 1999b) is important for memory consolidation.

It has also been reported that the JNK protein is involved in memory formation. For example, in one study, a JNK kinase inhibitor (SP600125) was administered in the dorsal CA1 region of the hippocampus at different times, demonstrating that administration at 60, 90, 180, 270, or 360 min after training produced amnesia when tested 24 h later (Bevilaqua et al. 2003). Immunoblot assays also revealed that c-Jun phosphorylated at serine 63 was decreased at 15 min after administration of the inhibitor in the same region, with no effect on other kinases in their phosphorylated form, such as ERK1/2 and p38-MAPK; observations at 60 min after inhibitor administration produced no changes in the same kinases (Bevilaqua et al. 2003).

The involvement of p38-MAPK proteins in long-term memory has also been described. Alonso et al. (2003) demonstrated that administration in CA1 of a p38-MAPK α and β inhibitor (SB203580) immediately after training induced impairment in memory consolidation. Western blot analysis further confirmed that levels of these phosphorylated proteins increased immediately after training.

The participation of ERKs in memory fixation has been explored, and it has been observed that G protein-coupled receptors and tyrosine kinases regularly transmit signals that stimulate the Raf/MEK/ERK cascade, which in turn activates CREB, among other transcriptional factors involved in the regulation of the synthesis of proteins necessary for the formation of new memories (Bernabeu et al. 1997a,b; Kim et al. 2013).

It has been reported that this pathway is also activated by NMDA receptors; for example, Cammarota et al. (2000) reported that in the hippocampus there is increased phosphorylation of ERK1/2 two hours after training in the IA task and that a NMDA receptor antagonist blocked the activation of the RAS/MEK/MAPK/Elk-1 signaling pathway in the hippocampus (CA1), producing impairment in long-term memory (Figure 1).

Walz et al. (2000) reported that the administration of nerve growth factor (NGF) in the dorsal hippocampus immediately after training produced facilitation of memory and proposed that the effect of NGF may be due in part to the activation of the Ras-MAPK pathway in the CA1 region during memory consolidation (Figure 1); previously, the activation of the MAPK pathway by the presence of NGF had been reported (Xing et al. 1998).

Alonso et al. (2002b) reported that administration of the brain-derived neurotrophic factor (BDNF) in the dorsal hippocampus 3 h after training facilitated long-term memory, and this effect was reversed by administration of a drug that blocked BDNF activity (PD098059). Furthermore, Western blot analysis confirmed that BDNF administration in the hippocampus increased ERK1/2 phosphorylation, which led them to propose the involvement of this pathway in memory formation. However, in another study using immunoblot techniques, the authors found that ERK1/2 activation around the time of training is not critical for long-term memory, only for short-term memory (Alonso et al. 2002a). Alonso et al. (2002c) utilized immunoblots and densitometric analyses found that aversive behavioral experiences are accompanied by rapid and transient activation of ERK/MAPKs, suggesting that these pathways play a role in the neural responses to stressful stimuli.

Regarding the involvement of this subfamily of MAPKs in other brain structures, Giovannini et al. (2005) used microdialysis to demonstrate that there is a release of acetylcholine in the medial prefrontal cortex (infralimbic region) and ventral hippocampus, which correlated with an increase in the number of neurons expressing phosphorylated ERKs (as determined with immunohistochemistry) in these same regions; although they did not evaluate long-term memory, they proposed that training induces the activation of this signaling cascade, thus participating in consolidation. Another work that reinforces the relationship between cholinergic activity and the ERK1/2 pathway is by Han and Kim (2003). They found that oral administration of Asiasari radix (traditional medicinal plant from Korea and China) induced memory facilitation in rats trained in the IA task. Using an ex vivo acetylcholinesterase assay and Western blot analysis, they evaluated the activity of cholinesterase and ERK1/2 in the hippocampus 1 h after the administration of Asiasari radix and found an increase of ERK1/2 protein and a decrease in the activity of cholinesterase, suggesting that these are mechanisms that participate in the formation of memory. Furthermore, Fornari et al. (2012) found an increased number of cells expressing immunoreactivity for phosphorilated ERK1/2 in the disgranular and agranular region of the insular cortex 30 min after training in the IA task, proposing that the increase in neuronal activity in these areas may be related to memory formation and novel characteristics of the experience.

Data related to other structures were reported by Rossato et al. (2004), who administered an ERK pathway blocker (U0 126) into the hippocampus, BLA, posterior parietal cortex, entorhinal cortex, or posterior cingulate cortex at 30, 90, 180, 270, or 360 min after training. They found that pharmacological blockade of the ERK pathway in these structures produced retrograde amnesia, but the time course of the effect differed across brain structures. The authors concluded that the activity of these kinases is important for long-term memory, proposing that consolidation is produced by the complex interaction among different brain structures.

Cammarota et al. (2008), using immunoblotting and densitometric quantification, reported an increase of phosphorylated ERK in the amygdala at 0 and 30 min after training; they found that this signal requires β-adrenergic receptor activity for memory consolidation. Phosphorylated ERK in the hippocampus (CA1 region) increased only at 30 min, and this increase was blocked by an NMDA receptor antagonist. These authors suggested that the amygdala and the hippocampus may play parallel roles in memory processes.

To study interactions between brain structures in IA, Roozendaal et al. (2009) found that administration of GR agonists into the medial prefrontal cortex (prelimbic and infralimbic regions) immediately after IA training produced, 15 min after infusion, an increase in ERK1/2 phosphorylation levels in the BLA, measured with Western blot techniques. Furthermore, they observed that ERK inhibition in the medial prefrontal cortex blocked the facilitation of memory induced by a GR agonist in the basolateral amygdala. The authors suggested that both structures have a bidirectional circuit involved in long-term memory formation.

2.4 CaMKII

The Ca²⁺ ion is a second messenger that activates several cell functions. Calmodulin (CaM) is a protein that binds Ca²⁺ to form the Ca²⁺/CaM complex, which activates different targets, including some Ca²⁺ channels and protein kinases (Swulius and Waxham 2008). Regarding the latter, there is a family of Ca²⁺/CaM-dependent kinases that phosphorylate serine, threonine, or tyrosine residues, also called CaM kinases (CaMKs) (Hook and Means 2001). The family includes proteins such as myosin light chain kinase (MLCK) and calcium-calmodulin-dependent kinases (CaMKs) I, II, and IV (Picciotto et al. 1993, 1996]).

The CaMKs are classified according to the number of substrates they have, so there are proteins with only one substrate, such as phosphorylase kinase, CaMKIII and MLCK, and proteins with many substrates, such as CaMKI, II and IV (Hook and Means 2001; Swulius and Waxham 2008). CaMKII has four main isoforms: α, β, γ, and δ. α and β isoforms that are mainly expressed in the brain (Vigil and Giese 2018; Zalcman et al. 2018). CaMKs are important in a wide variety of cellular functions. They have a major role in cognitive processes such as learning and memory, and CaMKII activity is closely related to memory consolidation of IA tasks (Izquierdo et al. 2000, 2006]).

CaMKII activity is closely related to IA memory formation. Intrahippocampal administration of treatments that inhibit CaMKII activity immediately or 30 min after training induces memory impairment of this task (Bevilaqua et al. 2005; Cammarota et al. 2004; Wolfman et al. 1994). It has also been reported that blocking CaMKII activity pharmacologically in the entorhinal cortex immediately after training results in memory impairment (Izquierdo et al. 2000; Vianna et al. 2001). The same effect has been observed when the inhibitor is administered to the amygdala, but the amnestic effect only occurs when the treatment is given immediately before or after training, indicating that the involvement of this kinase varies depending on the brain structure (Tan and Liang 1997; Wolfman et al. 1994).

Several studies have demonstrated increased CaMKII expression in the hippocampus within 30 min to 24 h after IA training (Bekinschtein et al. 2010; Cammarota et al. 1998, 2008]; Igaz et al. 2004a) (Table 1). This upregulation coincides with increased expression of the GluA1 subunit of AMPA receptors in the hippocampus, suggesting that CaMKII activity is responsible for receptor phosphorylation of GluA1 (Cammarota et al. 1998). Using Western blot analysis, Cammarota et al. (2008) reported that IA training induces CaMKII activation in the CA1 region of the dorsal hippocampus 30 min after training and found no changes in this kinase in the amygdala. Additionally, through pharmacological infusions and immunoblot analysis, they demonstrated that the involvement of the CaMKII pathway in memory consolidation requires NMDA receptor activity in the hippocampus. On the other hand, Bevilaqua et al. (2005) found increased quantity and phosphorylation of GluR1 and GluR2/3 (AMPA receptor subunits) after the IA training. However, this effect was reduced when they performed intra-CA1 infusions of the NMDA receptor antagonist D-(−)-2-amino-5-phosphonopentanoic acid (AP5) or the CaMKII inhibitor KN-93. The hippocampal NMDA receptor NR1 subunit expression increased after IA training, as did CaMKII levels and phosphorylated CaMKII (Moyano et al. 2004b).

In addition to the involvement of glutamatergic receptors, the role of serotonergic receptors in long-term memory of IA has been reported. Moyano et al. (2004a) explored the effect of 5-HT1A receptor activation on the consolidation of IA memory. They found that systemic administration before training of 8-OH-DPAT, an agonist to these receptors, induced amnesia, and this effect was reversed by co-administration of the antagonist (WAY-100635). The authors assessed with enzyme assays, the levels of CaMKII and phosphorylated CaMKII in the hippocampus and the level of PKA and protein phosphatase 1 (PP1) that dephosphorylates CaMKII. They reported that the serotonin agonist reduced PKA and phosphorylated CaMKII levels but increased PP1. Conversely, the co-administration of the antagonist and the agonist reversed this effect. The results suggest that activation of the 5-HT1A receptor disrupts memory consolidation, at least partially through PKA indirect regulation of CaMKII by phosphorylation/activation of PP1 (Figure 1).

The evidence presented in this section underlines the relevance of PKA, PKC, MAPK-ERK, and CaMKII activity in memory formation during IA training in different brain regions.

Figure 1 summarizes the hippocampal molecular changes involved in memory consolidation of IA training, providing a visual representation of how protein kinases converge in the cytoplasm and cell nucleus, leading to the activation of other molecules, such as CREB, and transcription genes such as c-fos and BDNF. These changes are known to be crucial for the neuronal structural and functional modifications required for memory storage (Alonso et al. 2002a,b; Chen et al. 2012; Giese and Mizuno 2013; Izquierdo et al. 2006; Zhong et al. 2018).

3 Protein kinase crosstalk and temporal dynamics during memory consolidation of IA

Several studies have reported temporal dynamics in kinase activity manifested in rats trained in the IA task. The temporal dynamics of PKA, PKC, MAPK, ERK, and CaMKII described in the hippocampus show that PKA is active in the first 30 min post-training and then at 3 and 6 h; PKC, MAPK, ERK, and CaMKII show activity in the first 2 h; ERK again at 24 h and CaMKII increases at 18 and 24 h (Table 1). Protein kinase phosphorylation reactions have been reported to be critical in the consolidation process, activating other intracellular and membrane proteins (Izquierdo et al. 2006; Micheau and Riedel 1999). It can be hypothesized that there may be a different role among kinases depending on their activation duration, as Micheau and Riedel (1999) suggested.

It is likely that multiple kinases operate simultaneously and sequentially during the formation of memory. While kinases often target different substrates, their combined effects on memory consolidation are determined by their crosstalk (Giese and Mizuno 2013; Izquierdo and McGaugh 2000; Izquierdo et al. 2006; McGaugh and Izquierdo 2000; Micheau and Riedel 1999; Shobe 2002). Several proposals have been developed to elucidate the crosstalk of protein kinases based on data from various behavioral tasks in different species and in vivo models such as long-term potentiation (LTP) (Giese and Mizuno 2013; Micheau and Riedel 1999), and some authors have even suggested molecular parallels between LTP and IA (Izquierdo and McGaugh 2000; Izquierdo et al. 2006; McGaugh and Izquierdo 2000; Shobe 2002).

Understanding the crosstalk of these protein kinases has provided insights into the molecular mechanisms involved in memory formation (Giese and Mizuno 2013; Izquierdo and McGaugh 2000; Izquierdo et al. 2006; McGaugh and Izquierdo 2000; Micheau and Riedel 1999; Shobe 2002). Protein kinase activity in memory processes is known to influence the regulation of synaptic transmission by altering the properties or densities of the receptors with which they interact and influences changes in the cytoskeleton, inducing changes in synaptogenesis (Giese and Mizuno 2013; Van der Zee 2015).

It has been proposed that the PKC, CaMKII, PKA, and MAPK kinase signaling pathways influence memory formation in a coordinated and sequential manner (Izquierdo and McGaugh 2000; McGaugh and Izquierdo 2000). Studies have indicated that in the first 30 min after training, activation of the PKC/B50/GAP43 pathway occurs in the hippocampus (Cammarota et al. 1997; Paratcha et al. 2000), which promotes the mobilization of synaptic vesicles in axon terminals (Cammarota et al. 1997). In dendrites, activation of the PKC pathway induces phosphorylation of glutamate receptors (Izquierdo and McGaugh 2000; Izquierdo et al. 2006), as well as phosphorylation of PKA and MAPK (Micheau and Riedel 1999; Roberson et al. 1999).

Training in the IA task induces Ca²⁺ entry into the cell through the activation of glutamate receptors, leading to an increase in CaMKII phosphorylation (both Ca²⁺ dependent and Ca²⁺ independent isoforms) (Cammarota et al. 1998). It has been reported that some CaMKII isoforms remain active despite Ca²⁺ staying at basal levels, indicating that these kinases continue to play a role in memory formation hours later (Bekinschtein et al. 2010). Phosphorylated CaMKIIs support the incorporation of the GluR1 subunit of AMPA receptors into dendrites, making synapses and memory consolidation more efficient (Micheau and Riedel 1999). It has been proposed that PKA and PKC pathway activity further potentiates this effect through CaMKII activation. Thus, PKA and PKC influence CaMKII activity, phosphorylating AMPA receptors (Shobe 2002).

The cAMP/PKA/CREB pathway displays two temporal windows of activity, one in the first minutes to 1 h and the second between 3 and 6 h. The latter window has been reported to correlate with dendritic increase (O’Malley et al. 1998). Its activity is modulated by dopaminergic, adrenergic, and serotonergic synapses (Bernabeu et al. 1997a; Izquierdo and McGaugh 2000).

Although the temporal activation of the kinases differs, it is possible to propose an interaction between the PKA, PKC, and MAPK pathways in CREB phosphorylation. The MAPK pathway phosphorylates CREB at serine 135, which coincides with the PKA target site. Both the PKA and PKC pathways have been reported to regulate MAPK activation (Roberson et al. 1999). In addition, studies indicate that the transcription factors p44- and p42-MAPKs, together with CREB, contribute to c-Fos production, these mechanisms being related to NMDA receptor activity (Izquierdo and McGaugh 2000). Another example of kinase interaction has been suggested by Izquierdo et al. (2006), where PKC, PKA, and CaMKII converge to phosphorylate CREB.

In addition, Izquierdo et al. (2006) proposed that the PKA/CREB and MAPK/CREB pathways involve monoaminergic receptors, which may have significant implications for processing the emotional component of IA, considering that highly emotional experiences tend to be better consolidated.

Among the experimental findings aimed at understanding the crosstalk among protein kinase activities in memory consolidation are those of Guerra et al. (2012). These authors determined that activation of the hippocampal NMDA receptor in rats trained in the IA task induced sequential signaling between kinases, where PKC activation was necessary to activate PKA/CREB. These mechanisms facilitated memory formation.

Dahleh et al. (2024) suggested that CREB phosphorylation is the principal mechanism involved in spermidine-induced memory formation and that CaMKIIα acts as a kinase that initializes the memory consolidation. However, CaMKIIα does not phosphorylate CREB directly. They showed the crosstalk among PKC, PKA, and CREB, mediated by CaMKII activation, induced by the administration of spermidine in IA consolidation. Their results demonstrated that post-training intrahippocampal co-administration of the CaMKII inhibitor (KN-62) and spermidine impeded memory enhancement in the IA task induced by spermidine. The co-administration of spermidine with KN-62 resulted in downregulation of the CaMKII/PKA/CREB pathway. However, the co-administration of KN-62 and spermidine did not alter the memory-facilitating effect of spermidine, nor the increased levels of PKC, indicating a simultaneous cascade in memory acquisition via PKC without modulation of CaMKII. These findings suggest that memory enhancement induced by spermidine administration involves crosstalk among CaMKII and PKA/CREB, with no involvement of PKC. Therefore, the authors proposed that PKC participates in an alternative crosstalk pathway to phosphorylate CREB.

The study of the interaction between protein kinases and their temporal dynamics during IA memory consolidation has been a point of interest, demonstrating that protein synthesis is an important mechanism that facilitates structural changes in the synapses related to memory formation. However, it should be noted that protein phosphorylation, carried out by protein kinases, is also involved in post-translational mechanisms (Micheau and Riedel 1999; Schmid et al. 1999; Sunyer et al. 2008), and these mechanisms have been little explored in rats trained in the IA task.

4 Protein kinases and their relationship with synaptic plasticity and memory consolidation

Synaptic plasticity is a mechanism reflected in the efficiency of synaptic communication and changes in neuronal architecture. As has already been reported, the activity of protein kinases generates changes in synaptic plasticity, which has led to the proposal that this activity influences the process of long-term memory (Giese and Mizuno 2013; Sweatt 2004; Van der Zee 2015).

Dendritic spines are the primary excitatory post-synaptic sites where Ca²⁺ often serves as the initial and most rapid signal, initiating most of the signaling cascades (Ohadi and Rangamani 2019; Ohadi et al. 2019; Popik et al. 2018). Changes in the morphology of dendritic spines have been linked to memory formation (Eyre et al. 2003; Leuner et al. 2003; Moser et al. 1994; O’Malley et al. 1998, 2000]), and protein kinases are commonly considered essential proteins involved in mediating these structural changes (Giese and Mizuno 2013; Komatsuzaki et al. 2012; Sweatt 2004; Van der Zee 2015).

It has been shown that interference with NMDA receptor activity by administration of ketamine, an NMDA antagonist, impairs spatial and emotional memory in pregnant rats and decreases hippocampal dendritic spine density and protein levels of phosphorylated PKA and ERK (Li et al. 2017). Similarly, the administration of propofol, a glutamate agonist at the level of NMDA receptors, reduces the levels of PKA and its target proteins, phosphorylated CREB and BDNF in the hippocampus of adult rats, and impairs memory (Zhong et al. 2018).

Pan et al. (2020) administered systemic aluminum maltol (a neurotoxin used in Alzheimer’s disease models) to rats and reported decreased levels of PKC and NMDA receptor subunits NMDAR1 and NMDAR2A, along with a reduced density of dendritic spines in hippocampal neurons. It has been reported that in the pre-synapse, PKC induces phosphorylation of ion channels and transporter proteins to regulate the release of neurotransmitters and that PKC participates in the incorporation of AMPA, NMDA, mGluR5 receptors in the post-synaptic membrane to induce synaptic changes (Callender and Newton 2017).

Rats trained in an aversive and spatial task exhibited increased mushroom-like dendritic spines in the hippocampus. Moreover, this effect was amplified with the administration of a PKC agonist (bryostatin) (Hongpaisan and Alkon 2007). Administering bryostatin during a spatial memory task restored mushroom-like dendritic spines and their synapses in aged rats. Additionally, this treatment led to cognitive performance similar to that of young rats. Finally, it was reported that bryostatin reversed alterations in inhibitory GABAergic post-synaptic currents in aged rats with learning disabilities (Hongpaisan et al. 2013).

It has been reported that training in the IA task induces the translocation of AMPA receptors from intracellular stores to the post-synaptic membrane in the CA1 region of the hippocampus, and this phenomenon is related to the activity of CaMKII present in the post-synaptic membrane (Cammarota et al. 2004). Additionally, it has been demonstrated that there is an increase in CaMKII autophosphorylation levels in a fraction of post-synaptic density protein enriched hippocampal neurons immediately, 30, and 60 min after training; it was proposed that IA training induces CaMKII translocation to post-synaptic terminals, derived from NMDA receptor activation (Bevilaqua et al. 2005).

Jafari et al. (2012) showed that GRs are localized in the dendritic spines of hippocampal neurons and that acute glucocorticosteroid treatment causes increases in pCofilin and pERK1/2; these molecules influence actin regulatory signaling pathways that stabilize cytoskeletal changes of spines. Other researchers demonstrated that the hippocampal GR is required for memory consolidation of the IA task, and this activation is coupled to phosphorylation of ERK1/2 as well as CaMKIIα. They also showed that pGR activation mediates the learning-dependent upregulation of Arc, subunit GluA1, and pSynapsin-1, indicating that they affect both pre-and post-synaptic mechanisms, suggesting that there is growth of new synaptic connections induced by IA learning task. These investigators proposed that CaMKIIα-BDNF-CREB synaptic plasticity pathways mediated by GR activation participate in memory consolidation (Chen et al. 2012).

The evidence presented in this section shows that activation of protein kinases plays an important role in synaptic plastic changes, involving dendritic spine remodeling probably related to memory consolidation.

5 Discussion

As we have seen throughout this review, there are several brain structures, such as the amygdala, insular cortex, cingulate cortex, parietal cortex, entorhinal cortex, prefrontal cortex, striatum, and hippocampus, involved in memory consolidation of the IA task. Several neurotransmitter systems are also known to be released after IA training, such as glutamate, acetylcholine, serotonin, GABA, dopamine, adrenaline, and neuromodulatory agents such as BDNF, indicating that they are involved in consolidation. In addition, second messenger cascades are activated, such as those described in the hippocampus; the IA task increases cGMP immediately and up to 30 min after training, while cAMP increases 30–180 min afterward. Blockade of the activity of these nucleotides has been shown to induce memory impairment, thus evidencing their involvement in memory formation (Bernabeu et al. 1996). Downstream of this internal signal in the cytoplasm of neurons is the activation of protein kinases, as exemplified in Figure 1, triggering intracellular events that are probably responsible for plastic changes at the synapse that support memory formation.

In this review, we propose that protein kinase activation pathways play an important role in the modulation of changes in neuronal architecture in the brain regions mentioned above. When protein kinases exert their effects, they trigger diverse intracellular pathways that amplify sensed signals by modifying synaptic efficiency. That is, 1) protein kinases influence synaptic transmission by altering ion channel properties or channel density, and 2) protein kinases promote modifications in the cytoskeleton by interacting with actin filaments, or regulating gene expression and protein synthesis, leading to structural changes (Callender and Newton 2017; Giese and Mizuno 2013; Micheau and Riedel 1999; Nelson and Alkon 2015; Shobe 2002).

As we have pointed out, research related to the hippocampus demonstrates varied temporal dynamics in the increase of kinase levels following IA training, suggesting that those that are increased in the early minutes and first hours after training are related to the amplification and integration of information, while those increased at longer intervals after training are involved in synaptic plasticity related to the formation of long-term memory (Izquierdo et al. 2006). However, it is important to mention that there are no studies on the IA task evaluating the dynamics of PKA and PKC occurring at 24 h or longer (see Table 1), nor are there studies describing a broad continuum of temporal dynamics of all kinases. To date, the literature has only reported a few time points; therefore, the variability in the time point at which measurements of changes in kinases were made impedes the direct comparison among studies.

It has been reported that the percent change of AMPA and NMDA receptors present in the hippocampus during the IA task increases immediately after training (Izquierdo and Medina 1997), where the percent change of AMPA receptors is much higher than that of NMDA receptors. There are also differences in their temporality since the highest expression of NMDA occurs at 1 h, and in the case of AMPA receptors it happens at around 3 h post-training (Izquierdo and Medina 1997; Izquierdo et al. 2006). These modifications of glutamatergic receptors allow the increase of intracellular calcium concentration followed by an increase of CaMKII before the first hour, permitting phosphorylation of AMPA receptors (Cammarota et al. 1998). In parallel to this activity, PKC and CaMKII activities are enhanced post-training, reinforcing the activity already initiated by glutamate receptors and inducing different molecular changes such as receptor mobilization and phosphorylation of several proteins including CREB (Cammarota et al. 1997; Carew and Sutton 2001; Dahleh et al. 2024; Izquierdo et al. 2006). However, it has been proposed that other receptors such as dopaminergic (Bernabeu et al. 1997a,b; Bevilaqua et al. 1997; Furini et al. 2014; Moncada et al. 2011), serotonergic (Bevilaqua et al. 1997; Moyano et al. 2004a, 2004b), GABAergic (Rossato et al. 2004) and adrenergic (Bevilaqua et al. 1997; Cammarota et al. 2008; Moncada et al. 2011) also interact with protein kinases in memory process. Protein kinases typically target diverse substrates, and their collective impact on memory consolidation is shaped by the crosstalk among them (Giese and Mizuno 2013; Izquierdo and McGaugh 2000; Izquierdo et al. 2006; McGaugh and Izquierdo 2000; Micheau and Riedel 1999; Shobe 2002).

The protein kinases are found in the cytoplasm, axonal boutons, and dendrites, each with different functions depending on their location. The effects of kinase activation, mediated by phosphorylation, can be divided into two categories: those that trigger transcriptional mechanisms in the nucleus and induce protein synthesis (Borodinova et al. 2017; Giese and Mizuno 2013; Nelson and Alkon 2015), and those that play a major role in post-translational changes, including modifications of dendritic spines (Borodinova et al. 2017; Mao and Wang 2016; Nelson and Alkon 2015; Penzes and Jones 2008).

An important phenomenon whose molecular mechanisms have barely been studied is the effect of intense training on memory. It has been amply described that interfering with brain activity produces marked impairments of memory consolidation of one-trial IA, commonly trained with relatively low or moderate foot shock intensity. In contrast, intense training protects against such impairments. Intense training produces high resistance to extinction, as evidenced by the long-lasting memory of the aversive conditioned response (e.g., Garín-Aguilar et al. 2014; Prado-Alcalá et al. 2012; Torres-García et al. 2017). It is well known that in humans, a single experience of a traumatic event is sufficient to produce post-traumatic stress disorder (PTSD) (Izquierdo et al. 2016; Lissek and van Meurs 2015; Souza et al. 2017); a hallmark of this condition is also the persistence of the aversive memory (Izquierdo et al. 2016). Since this feature parallels what is found after intense IA training, studying the molecular events underlying intense training might shed some light on this incapacitating illness.

PTSD may be associated with abnormal neural activity that could lead to high and permanent synaptic activity through the promotion of enhanced spinogenesis. Findings from our laboratory have provided compelling evidence that intense training recruits a higher number of neurons in the amygdala (Ruiz-López et al. 2021) and ventral striatum (González-Franco et al. 2017) than moderate training; thus, enhanced spinogenesis and recruitment of neurons are mechanisms worth exploring in relation to the genesis of PTSD.

In the search for the neurobiological basis for this resilient type of memory, it has been found that IA learning generated with a high foot shock induces a greater density of dendritic spines, specifically of the mushroom type, in the dorsomedial striatum, compared to rats trained with a lower foot shock intensity (Bello-Medina et al. 2016); this effect was also observed after retrieval of the task (Bello-Medina et al. 2022).

Compared to low or moderate training conditions, intense IA training induces a higher corticosterone release (González-Franco et al. 2017). It has been described that, in hippocampal slices, when PKA, PKC, ERK, MAPK, or PI3K (phosphoinositide 3-kinases) activity is blocked, the increased spinogenesis induced after corticosterone administration is also blocked (Komatsuzaki et al. 2012), but not when the slices are challenged with protein synthesis inhibitors, indicating that such spinogenesis depends on non-genomic mechanisms (Komatsuzaki et al. 2005). Intense IA training protects memory from the amnesia produced by protein synthesis inhibitors in both the hippocampus (Medina et al. 2019) and dorsal striatum (González-Franco et al. 2019). Thus, it may be the case that the high density of dendritic spines observed in the dorsal striatum following intense training does not depend on genomic mechanisms (Bello-Medina et al. 2016), but on post-translational changes, potentially involving protein kinases.

To the best of our knowledge, there is no published work addressing the involvement of kinase activity in conditions of high-intensity training, although progress has been made in the case of low or moderate IA training (Izquierdo and McGaugh 2000; Izquierdo and Medina 1997; Izquierdo et al. 2006, 2016]). Izquierdo´s group demonstrated that in several brain structures, protein kinase activity, acting in an orchestrated manner, is involved in different signaling pathways, making this a possible mechanism of memory formation. For example, they have proposed that the IA task induces the activation of glutamatergic receptors in the hippocampus causing an increase of intracellular calcium, as well as the phosphorylation of PKC and CaMKII one-hour post-training, and PKA and ERK1/2 three to 4 h after the IA task; these molecular changes have been observed in other models such as LTP (Izquierdo et al. 2006, 2016]). Furthermore, protein kinases have been shown to phosphorylate and activate many other proteins, including themselves, as well as various receptors, indicating that these mechanisms are required for the plastic changes necessary for the formation of memory of aversive experiences (Izquierdo et al. 2016) (Figure 2).

Figure 2:

The upper panel shows a schematic representation of the commonly used one-trial step-through and one-trial step-down inhibitory avoidance paradigms. The lower panel represents a hypothetical neurobiological mechanism underlying moderate (left side figure) and intense (right side figure) training, illustrating possible differences in signaling pathways (kinase activity), protein synthesis, and spinogenesis, suggesting dissimilar mechanisms involved in memory consolidation.

The involvement of kinase activity in memory consolidation of IA learning has dealt with training with low or moderate intensities of foot shock, but not with intense training. There is a growing literature showing that intense training impedes the retention deficits produced by a host of amnestic treatments. Therefore, it is possible that the published data regarding kinase activity and memory cannot be generalized to intense training. This is an issue that merits being studied.

A prevailing idea about memory formation indicates that it is dependent upon protein synthesis, which induces structural changes, particularly spinogenesis, that play a key role in memory consolidation. However, some evidence suggests that spinogenesis and memory consolidation depend on non-genomic mechanisms. We foresee that a growing number of studies will be derived from this innovative proposal.

6 Conclusions

In conclusion, this review has focused on research conducted in rats trained under low or moderate IA training conditions, a widely utilized model for studying the molecular mechanisms underlying long-term memory formation. Multiple brain structures, neurotransmitter and hormone systems, and signaling pathways integrate information, leading to synaptic plastic changes associated with the memory trace of the IA task. Recent experimental results from our laboratory have led us to propose that memory consolidation of intense training involves other mechanisms because moderate and high training conditions produce differential plastic changes (as evidenced through spinogenesis and neuronal activation). Also, intense training induces a long-lasting and resilient memory trace, akin to that described in situations of heightened fear and threat that lead to pathologies such as post-traumatic stress disorder in humans.

These observations highlight the close relationship between protein kinase pathways and structural changes, particularly spinogenesis, which most likely play a key role in the consolidation of highly aversive experiences. Further experiments are required to test the hypothesis that protein kinases, through non-genomic mechanisms, stimulate spinogenesis to strengthen the memory trace of enhanced learning experiences. Identifying the neurobiology of this type of memory will help to understand why high emotional memories persist over time.

Corresponding author: Andrea C. Medina, Departamento de Neurobiología Conductual y Cognitiva, Instituto de Neurobiología, Campus Juriquilla, Universidad Nacional Autónoma de México, Boulevard Juriquilla 3001, Juriquilla, Querétaro, Qro., 76230, Mexico, E-mail: acmedina@unam.mx

Funding source: Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México

Award Identifier / Grant number: Grant IN205222

Acknowledgments

I. M. was a recipient of a scholarship from Consejo Nacional de Ciencia y Tecnología (CONACYT) (1004224). We thank Norma Serafín, F. Javier Valles, and Michael Jeziorski for reviewing and helping us to improve the manuscript. Figures 1 and 2 were created with BioRender.com.

Research ethics: Not applicable.
Author contributions: All authors have contributed to the literature search and the writing of the manuscript, accepted responsibility for all content of this manuscript, and approved its submission.
Use of Large Language Models, AI and Machine Learning Tools: None declared.
Conflict of interest: The authors state no conflict of interest.
Research funding: Some experiments described in this article were financed by Dirección General de Asuntos del Personal Académico (Grant IN205222).
Data availability: Not applicable.

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Received: 2024-07-10

Accepted: 2024-09-08

Published Online: 2024-09-27

Published in Print: 2025-02-25

This work is licensed under the Creative Commons Attribution 4.0 International License.

Articles in the same Issue

https://doi.org/10.1515/revneuro-2024-0093

Keywords for this article

aversive memory; intense training; long-term memory; non-genomic mechanisms; protein kinases

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