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Hippocampal Cb2 receptors: an untold story

  • Robin Visvanathar , Maria Papanikolaou , Diana Aline Nôga , Marina Pádua-Reis , Adriano Bretanha Lopes Tort and Martina Blunder ORCID logo EMAIL logo
Published/Copyright: October 29, 2021
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Reviews in the Neurosciences
From the journal Reviews in the Neurosciences Volume 33 Issue 4

Abstract

The field of cannabinoid research has been receiving ever-growing interest. Ongoing debates worldwide about the legislation of medical cannabis further motivates research into cannabinoid function within the central nervous system (CNS). To date, two well-characterized cannabinoid receptors exist. While most research has investigated Cb1 receptors (Cb1Rs), Cb2 receptors (Cb2Rs) in the brain have started to attract considerable interest in recent years. With indisputable evidence showing the wide-distribution of Cb2Rs in the brain of different species, they are no longer considered just peripheral receptors. However, in contrast to Cb1Rs, the functionality of central Cb2Rs remains largely unexplored. Here we review recent studies on hippocampal Cb2Rs. While conflicting results about their function have been reported, we have made significant progress in understanding the involvement of Cb2Rs in modulating cellular properties and network excitability. Moreover, Cb2Rs have been shown to be expressed in different subregions of the hippocampus, challenging our prior understanding of the endocannabinoid system. Although more insight into their functional roles is necessary, we propose that targeting hippocampal Cb2Rs may offer novel therapies for diseases related to memory and adult neurogenesis deficits.

Keywords: adult neurogenesis; cannabinoids; endocannabinoid system; hippocampal Cb2 receptors; hippocampus; memory

Introduction

Peripheral Cb2 receptors – a half-truth

Our understanding of the endocannabinoid system (ECS) is continuously being shaped by novel discoveries of complex interactions and intricate processes. Since the initial description of the cannabinoid (Cb) receptors, namely the Cb1 receptors (Cb1Rs) (Matsuda et al. 1990) and the Cb2 receptors (Cb2Rs) (Munro et al. 1993), to the discoveries of the “blissful” substances anandamide (Devane et al. 1992) and 2-arachidonylglycerol (Mechoulam et al. 1995; Stella et al. 1997), emerging roles of the ECS in several brain processes have been recognized. Interestingly, the ECS encompasses both the central nervous system (CNS) and peripheral tissues (Mechoulam and Parker 2013). The Cb1R is widely distributed in the CNS, with abundant expression in the basal ganglia, cortex, cerebellum, and hippocampus, as shown by radiography (Herkenham et al. 1991), in situ hybridization (Mailleux and Vanderhaeghen 1992; Matsuda et al. 1993) and immunohistochemistry (Egertová and Elphick 2000; Tsou et al. 1998). These receptors are typically expressed on axon terminals and mediate retrograde signaling by endocannabinoids (Castillo et al. 2012). Much less is known about Cb2R-mediated signaling. In fact, for several years central Cb2Rs were largely overlooked and more attention was given to the peripheral Cb2Rs (Atwood and Mackie 2010; Kopach et al. 2012). Most cannabinoid research in the CNS to date has thus been focused on Cb1R. Recently, however, Cb2Rs have attracted considerable interest as potential modulators in drug-seeking behavior, pain, depression, anxiety, memory, neuroinflammation, and neurodegenerative diseases (Chen et al. 2017). During the last two decades, numerous studies have helped disperse the myth of Cb2Rs being exclusively expressed in the periphery. In situ hybridization and quantitative real-time PCR detected Cb2R mRNA in the hippocampus, cortex, cerebellum, brainstem, and midbrain of both rodents and nonhuman primates (García-Gutiérrez et al. 2012; Li and Kim 2015; Liu et al. 2009; Navarrete et al. 2012; Zhang et al. 2014). Moreover, Cb2R protein expression has been demonstrated for various brain regions (Ashton et al. 2006; Baek et al. 2008; Brusco et al. 2008; Gong et al. 2006; Van Sickle et al. 2005). Cannabinoid receptor expression has also been investigated in postmortem human brain tissue: Cb2R mRNA was found in the human prefrontal cortex while the expression of both Cb1R and Cb2R proteins was demonstrated in the cerebellum (Rodríguez-Cueto et al. 2014a,b).

Brain Cb2Rs are attractive therapeutic targets. Despite the low physiological expression, they are highly inducible under some pathological conditions, and their expression is quickly enhanced in the brain. The upregulation of Cb2Rs has been described in several disorders, including neurodegenerative diseases, brain injuries, and neuroinflammation. Among them, Parkinson’s disease (Gómez-Gálvez et al. 2016; Grünblatt et al. 2007; Navarrete et al. 2018), Alzheimer’s disease (AD) (López et al. 2018), post-traumatic stress disorder (PTSD) (Lisboa et al. 2019; Morena et al. 2018), traumatic brain injury (Tchantchou and Zhang 2013), vascular dementia (Luo et al. 2018), stroke (Zarruk et al. 2012), and neuroinflammation (Torres et al. 2011). The inducibility of Cb2R expression in pathological conditions was found mainly in the hippocampus, but there is also evidence for its occurrence across the CNS, including the cerebral cortex and the cerebellum (Figure 1A). The Cb2Rs are also induced in the spinal cord, in in vitro preparations for studying multiple sclerosis and in regions remotely connected to a primary site of focal brain damage during remote cell death (Figure 1B) (Askari and Shafiee-Nick 2019; Viscomi et al. 2009; Wen et al. 2015). Pathology-induced Cb2Rs were found in microglia, astrocytes, oligodendrocytes, and neurons. The activation of Cb2Rs in these cells modulates the release of several cytokines, which regulate immune function and inflammatory responses (Figure 1C).

Figure 1: Cb2R expression inducibility under pathological conditions. (A) Neuroinflammation (Torres et al. 2011), ischemia and stroke (Zarruk et al. 2012), Parkinson’s (Gómez-Gálvez et al. 2016; Grünblatt et al. 2007; Navarrete et al. 2018) and Alzheimer’s disease (AD) (López et al. 2018), post-traumatic stress disorder (PTSD) (Lisboa et al. 2019; Morena et al. 2018), traumatic brain injury (Tchantchou and Zhang 2013), vascular dementia (Luo et al. 2018), and remote cell death are related to the inducibility of Cb2Rs over the central nervous system (CNS), including neocortical, hippocampal and cerebellar regions. (B) Multiple sclerosis is associated with Cb2R upregulation in the spinal cord and in vitro models (Askari and Shafiee-Nick 2019; Wen et al. 2015). (C) Pathology-induced Cb2R modulates immunological response by regulating metabolic enzymes, cytokines release, and downstream functional molecules in microglia, astrocytes, oligodendrocytes, and neurons (Brusco et al. 2008; Campos et al. 2017; Gong et al. 2006). (COX-2) cyclooxygenase-2; (IL-1β) interleukin-1β; (IL-1ra) interleukin-1 receptor antagonist; (IL-1rl) interleukin-1 receptor, type I; (iNOS) inducible nitric oxide synthases; (LPS) lipopolysaccharide; (nNOS) neuronal nitric oxide synthases; (NF-κB) nuclear factor kappa-light-chain-enhancer of activated B cells; (TGF-β) transforming growth factor-β; (TNF-α) tumor necrosis factor-α.
Figure 1:

Cb2R expression inducibility under pathological conditions.

(A) Neuroinflammation (Torres et al. 2011), ischemia and stroke (Zarruk et al. 2012), Parkinson’s (Gómez-Gálvez et al. 2016; Grünblatt et al. 2007; Navarrete et al. 2018) and Alzheimer’s disease (AD) (López et al. 2018), post-traumatic stress disorder (PTSD) (Lisboa et al. 2019; Morena et al. 2018), traumatic brain injury (Tchantchou and Zhang 2013), vascular dementia (Luo et al. 2018), and remote cell death are related to the inducibility of Cb2Rs over the central nervous system (CNS), including neocortical, hippocampal and cerebellar regions. (B) Multiple sclerosis is associated with Cb2R upregulation in the spinal cord and in vitro models (Askari and Shafiee-Nick 2019; Wen et al. 2015). (C) Pathology-induced Cb2R modulates immunological response by regulating metabolic enzymes, cytokines release, and downstream functional molecules in microglia, astrocytes, oligodendrocytes, and neurons (Brusco et al. 2008; Campos et al. 2017; Gong et al. 2006). (COX-2) cyclooxygenase-2; (IL-1β) interleukin-1β; (IL-1ra) interleukin-1 receptor antagonist; (IL-1rl) interleukin-1 receptor, type I; (iNOS) inducible nitric oxide synthases; (LPS) lipopolysaccharide; (nNOS) neuronal nitric oxide synthases; (NF-κB) nuclear factor kappa-light-chain-enhancer of activated B cells; (TGF-β) transforming growth factor-β; (TNF-α) tumor necrosis factor-α.

Regional increases in Cb receptor expression have been shown to modulate the potency and efficacy of exogenous agonists at disease sites, theoretically allowing for targeted activation at the local of injury (Miller and Devi 2011). However, there has only been limited success in transitioning Cb2R agonists from preclinical studies to clinical trials (Dhopeshwarkar and Mackie 2014). But it should be noted that even for the case of Cb1Rs, which have been extensively studied through decades, there is a paucity of well-established clinical applications. This reflects the complex role of the ECS in modulating brain function and could indicate the need for improvement in preclinical models (An et al. 2020). Notwithstanding, Cb2Rs have remarkable advantages over Cb1Rs as potential therapeutic targets (Chen et al. 2017). In contrast to Cb1Rs, Cb2Rs are less prone to produce psychotropic effects, which have been a key point in the ongoing worldwide debates regarding the legislation of medical marijuana (Dhopeshwarkar and Mackie 2014). Moreover, Cb2Rs have lower expression levels and a more specific distribution than Cb1Rs in the brain. Thus, Cb2R ligands could offer therapeutic treatments without the adverse effects often seen with Cb1R-ligands (Onaivi et al. 2011). Furthermore, Cb2Rs can balance Cb1R activation effects since the former are expressed in neuronal somatodendritic areas, and the latter are predominantly expressed on neuronal terminals (An et al. 2020). Considering these characteristics, studies aiming to unveil the Cb2R role in the neurophysiology of specific brain regions may foster the development of clinically effective Cb2R-modulators, which will likely offer novel strategies for treating neuropsychiatric and neurological diseases.

In this review, we discuss recent developments in hippocampal Cb2R research. We selected the hippocampus as a major area of interest since it plays a crucial role in cognition, learning, and memory, which are important functions disrupted in neurodegenerative and neuroinflammatory diseases (Leuner and Gould 2010). Moreover, the layers, subregional differences, and cell populations within this structure are well-known, facilitating inferences about potential Cb2R roles in hippocampal activity. Although the function of hippocampal Cb2R is still largely unexplored, recent reports show that they modulate cellular and network excitability, suggesting a meaningful role in regulating hippocampal output. As will be argued below, further exploring the function of hippocampal Cb2R is an important step to understand the cognitive effects of both exogenous and endogenous cannabinoids.

Different cell populations express Cb2 receptors in the hippocampus

In a series of experiments, Onaivi and colleagues explored the distribution of Cb2Rs in the hippocampus, and found them to be broadly distributed among its different subregions (Brusco et al. 2008; Gong et al. 2006; Onaivi 2006; Onaivi et al. 2006) (Figure 2). Together, these experiments also provided the first evidence for the expression of hippocampal Cb2Rs in microglia, principal neurons and interneurons, which encouraged further research. Below we discuss the findings for each cell type individually.

Figure 2: Cb2R expression in the hippocampus. Several studies have attempted to quantify the expression of Cb2R protein in the hippocampus. In situ hybridization (red rectangles) and immunohistochemistry (green rectangles) revealed Cb2R expression in CA1 (Schmöle et al. 2015; Wu and Wang 2018), CA2 (Gong et al. 2006), CA3 (Stempel et al. 2016), dentate gyrus (DG) (Schmöle et al. 2015), and subiculum (SUB) (Gong et al. 2006). (so) stratum oriens; (sp) stratum pyramidale; (sr) stratum radiatum; (sm) stratum moleculare; (sg) stratum granulosum; (po) polymorphic layer.
Figure 2:

Cb2R expression in the hippocampus. Several studies have attempted to quantify the expression of Cb2R protein in the hippocampus. In situ hybridization (red rectangles) and immunohistochemistry (green rectangles) revealed Cb2R expression in CA1 (Schmöle et al. 2015; Wu and Wang 2018), CA2 (Gong et al. 2006), CA3 (Stempel et al. 2016), dentate gyrus (DG) (Schmöle et al. 2015), and subiculum (SUB) (Gong et al. 2006). (so) stratum oriens; (sp) stratum pyramidale; (sr) stratum radiatum; (sm) stratum moleculare; (sg) stratum granulosum; (po) polymorphic layer.

Cb2 receptors in microglia

The function of peripheral Cb2Rs as potent immune modulators has been clearly demonstrated (Basu and Dittel 2011; Cabral and Griffin-Thomas 2009; Racz et al. 2008; Turcotte et al. 2016). Accordingly, the fact that the CNS microglial cells express Cb2Rs is not surprising since they are the resident macrophages (Perry and Teeling 2013). Microglial Cb2R expression in mouse and rat hippocampi was first demonstrated using different Cb2R-specific antibodies (Brusco et al. 2008; Gong et al. 2006). More recent studies challenge some of the results previously shown by Onaivi and colleagues. For instance, when combining RNAscope, an ultrasensitive in situ hybridization technique, with immunostaining against the microglial marker Iba1, no overlap could be detected in the CA1 region of healthy rat hippocampi (Li and Kim 2015). Some publications also challenge the specificity of Cb2R antibodies, and overall results indicate that currently available antibodies may lack specificity and may lead to conflicting outcomes (Li and Kim 2015). Considering these results, more validating research needs to be conducted. It is worth noting that, usually, the experiments that failed in finding Cb2R expression in hippocampal cells (microglia, principal neurons, and interneurons) were conducted using healthy tissue, while inflammatory responses in the brain have been suggested to increase Cb2R and its mRNA expression (Guida et al. 2017; Luongo et al. 2010; Palazuelos et al. 2009; Walter et al. 2003). Hence, the absence of microglial Cb2R expression in healthy hippocampal tissue would not exclude a potential functional relevance of this receptor during pathological conditions.

Cb2 receptors in principal neurons

Most Cb2Rs in the CA1 region of the hippocampus are expressed in the principal neurons, which are the excitatory pyramidal cells (Li and Kim 2015; Onaivi 2006). The localization of Cb2Rs in these cells is primarily postsynaptic. Still, they can also be observed in the rough endoplasmic reticulum, Golgi apparatus, neuronal cytoplasm, and in dendrites near the plasma membrane (Brusco et al. 2008). These findings support that Cb2Rs are synthesized in the soma and subsequently transported to target dendrites. Interestingly, no expression occurs in axon terminals (Brusco et al. 2008), and since hippocampal Cb1Rs are mainly expressed presynaptically (Castillo et al. 2012; Kano et al. 2009; Katona et al. 1999; Monory et al. 2015), this indicates a functional difference between Cb1 and Cb2 receptors. Moreover, this also suggests that the notion of the ECS as a retrograde signaling system might not be complete (Castillo et al. 2012). The postsynaptic localization of Cb2Rs in principal cells thus reveals a more complex role for the ECS in the hippocampus than previously thought.

Cb2 receptors in interneurons

Hippocampal interneurons consist of a morphologically diverse group of cell types. It has been suggested that there are at least 21 different classes of interneurons in the CA1 region alone (Klausberger and Somogyi 2008). In this region, the Cb1Rs are found primarily in GABAergic interneurons (Tsou et al. 1999). In contrast, Cb2R mRNA is found in about 20% of both glutamatergic and nonglutamatergic cells in the CA1 (Li and Kim 2015). Whether there exists an overlap of Cb1R and Cb2R expression within specific interneuron types is still open for exploration. Further understanding the localization of Cb2R expression might add a new perspective on the action of cannabinoids in the CA1 region, as some of the functions previously thought to be mediated by Cb1R could potentially be due to overlooked Cb2 intra- and/or inter-neuronal signaling cascades.

Moving from expression to functionality

Correlation does not imply causation, a mantra for science. Similarly, expression does not denote function. Therefore, albeit evident that both Cb2R mRNA and protein can be found in the hippocampus, whether this has functional relevance is debatable, as we revisit below.

Synaptic function of hippocampal Cb2 receptors

Although the levels of Cb2R mRNA are significantly lower in the CNS than in the periphery (Onaivi 2006; Van Sickle et al. 2005), there is enough evidence to support a functional importance of Cb2R for hippocampal activity. Recently, Stempel et al. (2016) reported a Cb2R-dependent long-lasting hyperpolarization in CA2 and CA3 pyramidal cells (Stempel et al. 2016). The hyperpolarization depended on the sodium-bicarbonate co-transporter, illustrating an important mechanism of Cb2R activity. By directly affecting the membrane potential, Cb2R may thus act complementary to Cb1R as modulators of network excitability.

Traditionally, the functional effects of the ECS in the hippocampus have been credited to Cb1R, which modulate presynaptic neurotransmitter release (Monory et al. 2015). Depending on the neuronal cell type and brain region, the activation of Cb1R can have opposite effects, either increasing or decreasing excitability (Chevaleyre and Castillo 2003; Miraucourt et al. 2016; Winters et al. 2012). Whether this is also the case for Cb2R is an open question. In layers II and V of the medial entorhinal cortex, activation of Cb2R decreases the amplitude of spontaneous inhibitory postsynaptic currents through suppression of GABAergic transmission (Morgan et al. 2009). On the other hand, a recent study reported that inhibitory synaptic transmission is not affected by acute activation of Cb2Rs in CA1 but rather that chronic activation of Cb2Rs results in increased excitatory transmission (Kim and Li 2015). The regional or cell-specific factors underlying the different actions of Cb2Rs in the hippocampus and medial entorhinal cortex have yet to be identified.

As stated above, whether the low levels of Cb2Rs in CA1 are relevant to synaptic function under physiological conditions is still an open question (Kim and Li 2015; Li and Kim 2016a; Stempel et al. 2016). To further complicate matters, the postsynaptic localization of Cb2Rs has also been challenged. Namely, Morgan et al. (2009) observed no changes in the kinetics of miniature inhibitory postsynaptic currents in the presence of a selective Cb2R agonist, which would be expected if Cb2R were post-synaptically located (Morgan et al. 2009). Therefore, there are important unanswered questions regarding the synaptic function and localization of Cb2R, but still enough pieces of evidence suggesting a functional Cb2R role in the hippocampus, which could lead to new interpretations of the effects of exogenous and endogenous cannabinoids in this region.

Cb2 receptors and memory consolidation

As discussed above, there is evidence of upregulation of Cb2R in microglia as a response to neuroinflammation, but the functional consequences are not yet clear. In addition, Cb2R mRNA and protein expression are upregulated in AD, for which one of the hallmark features is hippocampal-dependent memory impairment. However, how do Cb2R relate to memory consolidation? Köfalvi et al. (2016) observed in hippocampal slices of both young and old healthy mice that Cb2R activation increases glucose transporters (GLUT) in hippocampal astrocytes and neurons. In contrast, these authors reported that the glucose uptake induced by Cb2R activation is impaired in a mouse model of AD (TgAPP mice). TgAPP mice present β-amyloid-burden and object recognition memory impairment. Interestingly, prolonged oral administration of JWH-133, a selective agonist of Cb2Rs, rescued hippocampal glucose uptake, diminished β-amyloid levels, and prevented the memory deficit in TgAPP mice (Köfalvi et al. 2016; Martín-Moreno et al. 2012). Dagon et al. (2007) induced hepatic encephalopathy in wild-type and Cb2R knockout mice. Hepatic encephalopathy is a neuropsychiatric syndrome caused by liver dysfunction and characterized by impaired glucose oxidative pathways in the brain, amnesia, and confusion. The authors found that treatment with Δ9-tetrahydrocannabinol (THC) increased AMP-activated protein kinase, which in turn stimulated GLUT expression and transport efficiency in the hippocampus. Interestingly, THC also prevented spatial working memory deficit assessed by the eight-arm maze in wild-type mice but not in Cb2R knockout animals (Dagon et al. 2007). Given that brain glucose availability controls cognition and memory in humans (Messier 2004) and that central metabolic boosting alleviates the cognitive symptoms of brain disorders (Branconnier 1983), the studies mentioned above support a role of hippocampal Cb2Rs in counteracting cognitive impairment via regulation of glucose uptake.

In Cb2R knockout mice, hippocampal-dependent long-term contextual fear memory is impaired while hippocampal-independent cued fear memory is not affected (Li and Kim 2016a). A follow-up study showed that knocking out the Cb2R gene decreases hippocampal excitatory synaptic transmission, long-term potentiation, and dendritic spine density, indicating that the endogenous activity of Cb2R contributes to the maintenance of synaptic function and regulates cognitive functions such as long-term memory (Li and Kim 2016b). These results suggest that the loss of Cb2R may lead to hippocampal-dependent memory deficits, though they should be interpreted with caution since compensatory mechanisms may occur in developmental knockout mice. Furthermore, these results were obtained using a general Cb2R knockout mouse line and it is therefore not possible to infer whether memory impairment was specifically due to the loss of Cb2Rs in the hippocampus. Subsequently, Li and Kim (2017) used either Cre-dependent overexpression of Cb2Rs or CRISPR-Cas9 genome-editing techniques to delete Cb2R gene in combination with the injection of adeno-associated viruses into the dorsal hippocampus of transgenic mouse lines. With this approach, they were able to investigate the role of Cb2Rs in specific cell populations (i.e., pyramidal cells, interneurons, and microglia) and found that increasing or decreasing the expression of Cb2Rs in microglia respectively enhances or impairs contextual fear memory (Li and Kim 2017). They also showed that disruption of Cb2R expression in CA1 pyramidal neurons enhances spatial working memory, while overexpression reduces anxiety levels as tested by the open field test (Li and Kim 2017). Noteworthy, in studies that genetically modulate Cb2R expression it is impossible to disentangle if the memory impairments are due to hindered consolidation, acquisition or retrieval. In this regard, despite the limitations in the current available Cb2R agonists/antagonists, pharmacological studies are more advantageous to investigate the functions of CB2R in specific memory phases.

Nasehi et al. (2017, 2018 reported that microinjection of a Cb2R agonist (Gp1a) into CA1 impairs aversive memory consolidation in rats and mice. Moreover, aversive memory consolidation was further impaired when simultaneously injecting muscimol (an ionotropic GABA receptor agonist), suggesting an interactive effect between Cb2 and GABAA signaling (Nasehi et al. 2017, 2018). This notion is also supported by Garcia-Gutiérrez and Manzanares (2011), who reported an upregulation of GABAA protein expression after chronic activation of Cb2Rs in the cortex. A more recent study showed that Gp1a infusion into CA3 also impairs aversive memory consolidation. This effect was increased by coinfusion of scopolamine (a nonselective antagonist of muscarinic acetylcholine receptors), suggesting that Cb2Rs can also interact with cholinergic signaling (Nasehi et al. 2020). The suggestion of an interaction between cannabinoid and cholinergic signaling during memory processing was made previously by Robinson et al. (2010), although without a direct mention of Cb2Rs. They reported that intraperitoneal administration of WIN55,212-2 (a nonselective cannabinoid receptor agonist) before spatial memory acquisition caused memory impairment through a mechanism that was independent of Cb1R, and that this impairment was reversed by coinfusion of a cholinesterase inhibitor (Robinson et al. 2010). Similarly, studies in rats showed that cannabidiol disrupts consolidation of (specific and generalized) fear memories via Cb2R localized in the dorsal hippocampus (Raymundi et al. 2020; Stern et al. 2017).

It should be noted, however, that in addition to the studies showing that activating Cb2R signaling has disruptive effects on memory, there is also evidence for heightened Cb2R activity improving spatial and fear memory. Chronic treatment with Cb2R agonists and Cb2R upregulation could rescue spatial memory deficits in mouse models of vascular dementia or AD (Çakır et al. 2019; Lou et al. 2017; Wu et al. 2017). Moreover, Ratano et al. (2018) showed that the endocannabinoid 2-arachidonoilglycerol (2-AG) enhanced memory consolidation in a inhibitory avoidance task through a Cb2R-dependent modulation of mTOR signaling. In a previous study of the same group, they also showed that blocking Cb2R signaling tended to impair fear memory retention (Ratano et al. 2017). Consistently, chronic treatment with systemic Cb2R antagonist aggravated fear memory loss caused by orthopedic surgery (Sun et al. 2017). Nevertheless, downregulation of Cb2R expression in hippocampal cells has been associated with impaired spatial memory, object recognition, and fear conditioning acquisition and retention (Tang et al. 2017).

To summarize, it is clear that hippocampal Cb2Rs do influence memory, but contradictory results have been reported regarding the exact role of these receptors on memory consolidation and disruption. While Cb2R gene overexpression in the dorsal hippocampus enhanced fear conditioning, acute Cb2R agonism in the same region impaired fear conditioning consolidation (Li and Kim 2017; Raymundi et al. 2020). Nevertheless, increasing Cb2R activity in CA1 and CA3 impaired memory consolidation in inhibitory avoidance, but systemic Cb2R agonism enhanced memory retention in this same task (Nasehi et al. 2017, 2018, 2020; Ratano et al. 2018). In the Morris water maze, one study reported impaired spatial memory after treatment with a potent cannabinoid receptor agonist (Robinson et al. 2010), but several others showed improvement of spatial learning and prevention of memory deficits with selective Cb2R agonism (Çakır et al. 2019; Lou et al. 2017; Sun et al. 2017; Wu et al. 2017) (for an overview, see Table 1). These results suggest that Cb2R activation differently modulates aversive and neutral memories. Consistently, Cb2R mRNA transcripts in the DG and CA1 regions of the dorsal hippocampus were shown to be increased in stressed and anxious mice, further supporting the inducibility of Cb2R expression and indicating a role in coping mechanisms (Robertson et al. 2017). On the other hand, most studies using Cb2R knockout or antagonism showed impaired neutral, aversive, and spatial memory (see Table 2). But there is also evidence for contrasting promnesic and amnesic effects of Cb2R knockout on the Y-maze and fear conditioning, respectively (Li and Kim 2016b). Therefore, Cb2Rs modulate memory and behavior, as well as anxiety and stress, but less is known about their specific role and the exact mechanisms underlying their function (Figure 3). With increasing research interests and emerging techniques such as optogenetics and DREADDs, we hope that these questions will be addressed soon.

Table 1:

Cb2R overexpression and agonism effects on memory and behavior.

Model Behavior test Effect Reference
JWH-133 (0.2 mg/kg), intraperitoneal (IP) injections for 13 days, Okadaic acid (OKA) Alzheimer’s Disease (AD) model Sprague–Dawley rats, male Morris Water Maze Reduced neurodegeneration, neuroinflammation, and spatial memory impairment in the OKA-induced AD model Çakır et al. (2019)
∆9-tetrahydrocannabinol (THC) (0.1 mg/kg/day for five days), IP injection, Sabra mice, adult, female Eight-arm Maze Prevented spatial work memory deficit caused by liver failure Dagon et al. (2007)
JWH-133 (0.2 mg/kg/day in the drinking water for four months), TgAPP transgenic mice, adult, male Object Recognition Rescued memory deficit Köfalvi et al. (2016) and Martín-Moreno et al. (2012)
Overexpression in interneurons (CA1), Gad2-Cas9 mice, 2–3 months Y-Maze, Fear Conditioning, Tail Suspension, Open Field No effect Li and Kim (2017)
Overexpression in pyramidal neurons (CA1), Camk2a-Cas9 mice, 2–3 months Open Field Reduced anxiety levels Li and Kim (2017)
Overexpression in microglia (CA1), Cx3cr1-Cas9 mice, 2–3 months Fear Conditioning Enhanced contextual fear memory Li and Kim (2017)
β-caryophyllene (BCP) (16, 48, and 144 mg/kg), IP injection, Sprague-Dawley rats, adult, male Morris Water Maze (50 days after bilateral carotid artery clamping) Improved spatial learning and memory Lou et al. (2017)
GP1a (150 ng/rat), post-training, intra-CA1 microinjection, Wistar rats, adult, male Inhibitory Avoidance Impaired memory consolidation Nasehi et al., (2017)
GP1a (100 μg/mouse), post-training intra-CA1 microinjection, NMRI mice, adult, male Inhibitory Avoidance Impaired memory consolidation Nasehi et al. (2018)
GP1a (10 and 100 μg/mouse), post-training intra-CA3 microinjection, NMRI mice, adult, male Inhibitory Avoidance Impaired memory consolidation Nasehi et al. (2020)
2-arachidonoylglycerol (2-AG) (5 mg/kg), IP injection, Sprague–Dawley rats, adult, male Inhibitory Avoidance Enhanced memory retention Ratano et al. (2018)
CBD (10–30 pmol), intradorsal hippocampus injection, immediately, 1 or 3 h after fear conditioning, Wistar rats, adult male Fear Conditioning Impaired contextual fear memory consolidation Raymundi et al. (2020)
WIN55,212-2 (1 and 3 mg/kg), IP injection 30 min prior to each daily training session, lister Hooded rats, adult, male Morris Water Maze Impaired spatial memory Robinson et al. (2010)
JWH-133 (2 mg/kg, every 24 h post orthopedic surgery), IP injections, C57BL/6 mice, adult Training preoperative, Fear Conditioning (30 min after injection) Attenuated surgery-induced memory loss Sun et al. (2017)
MDA7 (14 mg/kg every second day for five months), IP injection, APP/PS1 mice, adult, female Morris Water Maze Improved spatial memory Wu et al. (2017)
Table 2:

Cb2R knockout and antagonism effects on memory and behavior.

Model Behavior test Effect Reference
Cb 2 R knockout mice (C57BL/6J background), 2–4 months Fear Conditioning, Y-Maze Impaired contextual long-term memory, enhanced spatial working memory Li and Kim (2016)
Disruption of Cnr2 gene expression in interneurons (CA1), Gad2-Cas9 mice, 2–3 months Y-Maze, Fear Conditioning, Tail Suspension, Open Field No effect Li and Kim (2017)
Disruption of Cnr2 gene expression in pyramidal neurons (CA1), Camk2a-Cas9, 2–3 months Y-Maze Enhanced spatial working memory Li and Kim (2017)
Disruption of Cnr2 gene expression in microglia (CA1), Cx3cr1-Cas9, 2–3 months Fear Conditioning Decreased contextual fear memory Li and Kim (2017)
AM630 (75 and 100 ng/rat), post-training, intra-CA1 microinjection, Wistar rats, adult, male Inhibitory Avoidance Impaired memory consolidation Nasehi et al. (2017)
AM630 (1, 10, and 100 μg), post-training, intra-CA3 microinjection, NMRI mice, adult, male Inhibitory Avoidance No effect Nasehi et al. (2020)
SR144528 (0.1 mg/kg), IP injection, Sprague–Dawley rats, adult, male Inhibitory Avoidance Tended to impair fear memory retention Ratano et al. (2017)
AM630 (0.3 mg/kg), IP or dorsal hippocampus injection, Wistar rats, 13–15 weeks, male Fear Conditioning Prevented the disrupting effects of cannabidiol on fear memory consolidation Stern et al. (2017)
AM630 (3 mg/kg, every 24 h post orthopedic surgery), IP injections, C57BL/6 mice, adult Training preoperative, Fear Conditioning (30 min after injection) Aggravated surgery-induced memory loss Sun et al. (2017)
miR-139 (3 mM), intradentate gyrus microinjection, SAMP8 Alzheimer’s Disease mouse model, six months old Morris Water Maze, Novel Object Recognition, Contextual Fear Conditioning Impaired spatial memory acquisition and retention, impaired novel object recognition, impaired fear conditioning Tang et al. (2017)
Figure 3: Cellular mechanisms of Cb2R function in a variety of expression systems and animal species. Activation of Cb2Rs has a variety of downstream effects via different pathways. These effects are mostly mediated by the activation of the coupled G-protein (represented by its α, β, and γ subunits). Cb2R activation can: (1) mediate plasticity in hippocampal CA3 principal neurons via a G-protein and Na+-dependent modulation of the sodium/bicarbonate co-transporter (NBC) (Stempel et al. 2016); (2) lead to a G-protein gated inward rectifying potassium channel (GIRK) mediated cell-autonomous hyperpolarization (Stumpf et al. 2018); (3) through phospholipase C (PLC) production, lead to Ca2+ release via IP3 which in turn leads to the opening of Ca2+-activated Cl− channels (CACCs) in layer II/III pyramidal neurons of the rat medial prefrontal cortex (den Boon et al. 2012); (4) negatively affect the production of adenylyl cyclase, which, through decreased cyclic adenosine monophosphate (cAMP) production results in reduced activation of protein kinase A (PKA) (Dhopeshwarkar and Mackie 2014); (5) mediate suppression of voltage-gated calcium channels (VGCCs) via reduced activation of PKA (Qian et al. 2017); (6) cause increased phosphorylation of p38 MAPK, JNK1 and JNK2 (Neves et al. 2018); (7) mediate upregulation of the PI3K/Akt pathway, increasing the activity of mTORC1 (composed by mTOR, Raptor, Deptor, mLST8, PRAS40, Ttti1, and Tel2), which in turn inhibits the cyclin-dependent kinase inhibitor p27Kip1 (Cao et al. 2018; Palazuelos et al. 2012); (8) through activation of sphingomyelin phosphodiesterase (SMase), can result in increased ceramide production (Askari and Shafiee-Nick 2019). For full reviews of Cb2R function mechanisms and therapeutic potentials, see Aghazadeh Tabrizi et al. (2016) and Cassano et al. (2017). Cb2R crystal structure taken from RCSB Protein Data Bank (https://www.rcsb.org/structure/5ZTY) (Li et al. 2019).
Figure 3:

Cellular mechanisms of Cb2R function in a variety of expression systems and animal species. Activation of Cb2Rs has a variety of downstream effects via different pathways. These effects are mostly mediated by the activation of the coupled G-protein (represented by its α, β, and γ subunits). Cb2R activation can: (1) mediate plasticity in hippocampal CA3 principal neurons via a G-protein and Na+-dependent modulation of the sodium/bicarbonate co-transporter (NBC) (Stempel et al. 2016); (2) lead to a G-protein gated inward rectifying potassium channel (GIRK) mediated cell-autonomous hyperpolarization (Stumpf et al. 2018); (3) through phospholipase C (PLC) production, lead to Ca2+ release via IP3 which in turn leads to the opening of Ca2+-activated Cl− channels (CACCs) in layer II/III pyramidal neurons of the rat medial prefrontal cortex (den Boon et al. 2012); (4) negatively affect the production of adenylyl cyclase, which, through decreased cyclic adenosine monophosphate (cAMP) production results in reduced activation of protein kinase A (PKA) (Dhopeshwarkar and Mackie 2014); (5) mediate suppression of voltage-gated calcium channels (VGCCs) via reduced activation of PKA (Qian et al. 2017); (6) cause increased phosphorylation of p38 MAPK, JNK1 and JNK2 (Neves et al. 2018); (7) mediate upregulation of the PI3K/Akt pathway, increasing the activity of mTORC1 (composed by mTOR, Raptor, Deptor, mLST8, PRAS40, Ttti1, and Tel2), which in turn inhibits the cyclin-dependent kinase inhibitor p27Kip1 (Cao et al. 2018; Palazuelos et al. 2012); (8) through activation of sphingomyelin phosphodiesterase (SMase), can result in increased ceramide production (Askari and Shafiee-Nick 2019). For full reviews of Cb2R function mechanisms and therapeutic potentials, see Aghazadeh Tabrizi et al. (2016) and Cassano et al. (2017). Cb2R crystal structure taken from RCSB Protein Data Bank (https://www.rcsb.org/structure/5ZTY) (Li et al. 2019).

Cb2 receptors and hippocampal adult neurogenesis

Previously we discussed the expression and some of the functions of Cb2R present in fully differentiated hippocampal cells. However, what about the hippocampal neural progenitor cells? For decades, scientists believed that the adult brain did not generate new neurons. This belief persisted until Altman and Das (1965) first reported neurogenesis in the DG of adult rodents, a finding that was later confirmed by several studies (Gonçalves et al. 2016; Jorgensen 2018). Currently, it is widely accepted that hippocampal adult neurogenesis happens in the subgranular zone of the DG of humans and several other vertebrates (Gonçalves et al. 2016; Jorgensen 2018). This process has been associated with memory and learning (Cameron and Glover 2015; Deng et al. 2010), mood disorders (Jorgensen 2018; Snyder et al. 2011), and neurological diseases (Horgusluoglu et al. 2017).

In the last decades, several studies have shown an important role of Cb2R in hippocampal adult neurogenesis. First, Palazuelos et al. (2006) used both in vitro and in vivo approaches to show that (1) Cb2R are expressed in both developmental and adult neural progenitor cells, and this expression is reduced after cell differentiation; (2) ablation of Cb2R signaling through knockout impairs adult neurogenesis; and (3) Cb2R activation increases hippocampal adult neurogenesis (Palazuelos et al. 2006). Then, in a follow-up study, Palazuelos et al. (2012) reproduced their previous results and extended them by showing that Cb2R promotes adult neurogenesis through the activation of the PI3K/Akt/mTORC1 pathway. This results in the inhibition of the cyclin-dependent kinase inhibitor p27Kip1, a protein that inhibits the G1-S phase transition in neural progenitor cells (Palazuelos et al. 2012). Later, Avraham et al. (2014) showed that Cb2R activation could reverse the deficits in hippocampal adult neurogenesis caused by the human immunodeficiency virus (HIV) glycoprotein 120 (Gp120) and could thus be a potential mechanism to treat HIV-associated neurocognitive disorders (Avraham et al. 2014). On the other hand, a recent study by Rodrigues et al. (2017) partially contradicted the previously mentioned results by showing that activation of Cb2Rs alone is not enough to induce the proliferation of DG neural precursor cells. Instead, activation of both Cb2Rs and Cb1Rs was necessary to induce this proliferation. Furthermore, they showed that, although Cb2R agonism is enough to induce differentiation of DG neural precursor cells, Cb1R signaling is still needed since its blockade prevents the effect of Cb2R agonism. Finally, they suggest the formation of Cb2R-Cb1R heteromers in these cells, which could be controlling neuronal differentiation (Rodrigues et al. 2017). Moreover, another recent study showed that Cb2R-deficient mice have normal hippocampal adult neurogenesis, suggesting that Cb2R signaling might not be necessary for basal hippocampal adult neurogenesis (Mensching et al. 2019). However, since the animals used in this study were constitutive knockouts, compensatory mechanisms might have influenced the results.

In sum, these studies strongly suggest that Cb2R signaling is important to control/modulate hippocampal adult neurogenesis. However, it is still not fully clear if it acts alone or in conjunction with Cb1R signaling or the specific mechanisms involved. Thus, further experiments are necessary to address these questions and whether Cb2R signaling is necessary for basal hippocampal adult neurogenesis or is only recruited in specific situations.

Concluding remarks and future perspectives

There is now enough data to support not only the existence but also the functional relevance of hippocampal Cb2Rs, which challenges our prior understanding of ECS action in the CNS and warrants further exploration. Hopefully, modern techniques will offer more robust approaches to answering some of the outstanding questions and shed light on the contradictory results in the literature. Among them, we should address the suggested postsynaptic localization of hippocampal Cb2Rs, which would crucially differentiate them from presynaptic Cb1Rs. Both light- and electron microscopy may help in this regard, and even more advanced techniques such as super-resolution microscopy could produce robust results (Cristino et al. 2017). Moreover, it is worth noting that the studies reviewed by us reported the discovery and active presence of Cb2Rs in the mammalian brain. Still, more quantitative approaches are needed to provide information to support differences in Cb2R expression along the hippocampal subregions and between their ventral and dorsal portions. This would improve the discussion of the functions of hippocampal Cb2Rs since the dorsal and ventral parts differently contribute to memory, anxiety, neurogenesis, and related pathologies (Fanselow and Dong 2010; Nadel et al. 2013). Until now, the most common approach for studying Cb receptor activity has been through pharmacology, with a large degree of uncertainty regarding the specificity of the compounds used (Console-Bram et al. 2012). Novel Cb2R-specific compounds and emerging transgenic tools now offer more targeted methods (Bickle 2016; Nevalainen 2014), and further combining these tools with current knowledge of regional and neuronal diversity should generate significant new insights.

The Cb2Rs may play a crucial role in regulating hippocampal-dependent memory formation and adult hippocampal neurogenesis, particularly during neuroinflammatory conditions where Cb2Rs are upregulated. The properties of low expression but high-inducibility during pathological conditions should incite more research on therapeutic strategies with selective Cb2R-modulators, especially considering their lower psychoactive effects than those of Cb1R-ligands (Chen et al. 2017). Further exploring hippocampal Cb2Rs should not only increase our understanding of the ECS but also contribute to the debate on the legislation of medical cannabis that currently concerns several countries worldwide. The emerging field of hippocampal Cb2Rs provides avenues for exploration and discovery; insightful times lie ahead.

Outstanding questions

  1. Is there a functional relationship between central Cb1 and Cb2 receptors? Can they form heteromers? If so, are they present in adult cells and what would be the functional implications?

  2. Are Cb2Rs mostly expressed postsynaptically? If so, should we replace the retrograde signaling view of the ECS in the CNS by a more complex signaling dynamics?

  3. How are Cb2Rs expressed in different hippocampal subregions and neuronal cell types? Would they mark a specific subset of interneurons? And what is the balance of expression between immune and nonimmune cells?

  4. What are the mechanisms of action of Cb2Rs in the hippocampus? Would the activity of Cb2Rs in microglia also influence network states?

  5. Is there a therapeutic role for Cb2R ligands, through orthosteric or allosteric binding, in neurodegenerative or neuroinflammatory diseases?

Corresponding author: Martina Blunder, Behavioral Neurophysiology, Department of Neuroscience, Biomedical Center, Uppsala University, Husargatan 3, 751 23, Uppsala, Sweden, E-mail:

Funding source: Swedish Research Council 2017-05021

Funding source: Fredrik och Ingrid Thurings Stiftelse

Funding source: Stiftelse Lars Hiertas Minne

Funding source: Åhlén-stiftelse

Funding source: Svenska Läkaresällskapets forskningsfonder

Funding source: Gunvor och Josef Anérs Stiftelse

Funding source: Emil och Ragna Börjessons Stiftelse

Funding source: Hjärnfonden

Funding source: Swedish Foundation for International Cooperation in Research and Higher Education

Funding source: Brazilian National Council for Scientific and Technological Development

Funding source: Brazilian Coordination for the Improvement of Higher Education Personal

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: This work was supported by the Swedish Research Council (Vetenskapsrådet, 2017-05021), Fredrik och Ingrid Thurings Stiftelse, Stiftelse Lars Hiertas Minne, Åhlén-stiftelse, Svenska Läkaresällskapets forskningsfonder, Gunvor och Josef Anérs Stiftelse, Emil och Ragna Börjessons Stiftelse, Hjärnfonden, the Swedish Foundation for International Cooperation in Research and Higher Education (STINT), the Brazilian National Council for Scientific and Technological Development (CNPq), and the Brazilian Coordination for the Improvement of Higher Education Personal (CAPES) through the international cooperation program CAPES/STINT. The funders had no role in design, decision to publish, or preparation of the manuscript.

  3. Conflict of interest statement: The authors declare no conflicts of interest regarding this article.

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Received: 2021-08-19
Accepted: 2021-10-01
Published Online: 2021-10-29
Published in Print: 2022-06-27

© 2021 Robin Visvanathar et al., published by De Gruyter, Berlin/Boston

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

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https://doi.org/10.1515/revneuro-2021-0109
Keywords for this article
adult neurogenesis; cannabinoids; endocannabinoid system; hippocampal Cb2 receptors; hippocampus; memory
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BY 4.0

Articles in the same Issue

  1. Frontmatter
  2. Monoaminergic hypo- or hyperfunction in adolescent and adult attention-deficit hyperactivity disorder?
  3. Immune modulations and immunotherapies for Alzheimer’s disease: a comprehensive review
  4. Current uses, emerging applications, and clinical integration of artificial intelligence in neuroradiology
  5. Central neuroinflammation in Covid-19: a systematic review of 182 cases with encephalitis, acute disseminated encephalomyelitis, and necrotizing encephalopathies
  6. Hippocampal Cb2 receptors: an untold story
  7. The protective effects of activating Sirt1/NF-κB pathway for neurological disorders
  8. Putative neural consequences of captivity for elephants and cetaceans
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