Band 25, Heft 2

Recent studies have advanced our understanding of the role of the cerebellum in non-motor behaviors. Abnormalities in the cerebellar structure have been demonstrated to produce changes in emotional, cognitive, and social behaviors resembling clinical manifestations observed in patients with autism spectrum disorders (ASD) and schizophrenia. Several animal models have been used to evaluate the effects of relevant environmental and genetic risk factors on the cerebellum development and function. However, very few models of ASD and schizophrenia selectively target the cerebellum and/or specific cell types within this structure. In this review, we critically evaluate the strength and weaknesses of these models. We will propose that the future progress in this field will require time- and cell type-specific manipulations of disease-relevant genes, not only selectively in the cerebellum, but also in frontal brain areas connected with the cerebellum. Such information can advance our knowledge of the cerebellar contribution to non-motor behaviors in mental health and disease.

In recent years, it has become evident that many neurotransmitters and endogenous ligands differentially modulate synaptic γ-aminobutyric acid type A receptors (sGABA A Rs) and extrasynaptic GABA A R (eGABA A Rs). In this mini-review, we will summarize the available evidence on the ability of the monoamines serotonin (5-HT), noradrenaline (NA), and, in particular, dopamine (DA) to alter the functional response of eGABA A Rs, thus either increasing or decreasing tonic GABA A inhibition. Although this field of research is still in its infancy, it has already been demonstrated that eGABA A Rs show a nucleus-selective and neuronal-type-selective regulation by monoamines in a way that differs from that of sGABA A Rs. Further work will undoubtedly advance our knowledge of the intricate talk between monoamines and eGABA A R and may ultimately provide new leads for the treatment of neurological and neuropsychiatric disorders, where alteration in GABA A R function is one of the underlying causes.

It is well established that the reinforcing properties of nicotine (NIC) depend on its action on nicotinic acetylcholine receptors expressed by brain neurons. However, when administered systemically, NIC first phasically activates nicotinic receptors located on the afferents of sensory nerves at the sites of drug administration before reaching the brain and directly interacting with central neurons. While this peripheral action of NIC has been known for years, it is usually neglected in any consideration of the drug’s reinforcing properties and experience-dependent changes of its behavioral and physiological effects. The goal of this work was to review our recent behavioral, electrophysiological, and physiological data suggesting the critical importance of peripheral actions of NIC in mediating its neural effects following acute drug exposure and their involvement in alterations of NIC effects consistently occurring following repeated drug exposure. Because NIC, by acting peripherally, produces a rapid sensory signal to the central nervous system that is followed by slower, more prolonged direct drug actions in the brain, these two pharmacological actions interact in the central nervous system during repeated drug use with the development of Pavlovian conditioned association. This within-drug conditioning mechanism could explain the experience-dependent changes in the physiological, behavioral, and human psychoemotional effects of NIC, which, in drug-experienced individuals, always represent a combination of pharmacological and learning variables.

Experience-dependent remodeling of synaptic structure and function underlies information storage in the mammalian central nervous system. Although accumulating evidence suggests synergistic roles of long-term depression (LTD) and long-term potentiation (LTP) in cerebellar motor learning, their structural correlates and operational mechanisms have not been clearly addressed. A recent three-dimensional electron microscopic study provides insight for a potential complementary interplay between LTP and LTD in local dendritic segments of Purkinje cells of motor skill-trained animals. Complex motor skill training induced strengthening of a subset of parallel fiber synapses onto Purkinje cells by forming multiple-synapse boutons (MSBs) contacting spine pairs arising from the same dendrite, whereas MSB-neighboring synapses were weakened by reducing the size of the postsynaptic density. Here, we discuss these orchestrated structural modifications of neighboring synapses that may sharpen synaptic weight contrast in local dendritic segments, leading to enhanced signal-to-noise ratio for optimal motor skill retention.

The universality and vitality of calcium ions are implicit from its diverse physiological functions, from regulation of enzymes to synaptic plasticity and memory. However, overloading of these ions could result in life-threatening degenerative disorders. Calcium channels, which are involved in the transport of calcium ions, are targeted and blocked to prevent its overload, favoring vascular relaxation. Besides this primary action, calcium channel blockers (CCBs) also genuinely exhibit cognitive-enhancing abilities and reduce the risk of dementia, especially of Alzheimer’s type. Alzheimer’s disease (AD) is triggered by the disruption of calcium homeostasis, which underlies the observed progressive cognitive decline that occurs in this neurodegenerative disorder. Fortunately, CCB is expected to offer neuroprotection and additionally demonstrate antiamyloid, antitau, antiphospholipase, antiplatelet, antioxidant, and anti-inflammatory activity, a solitary solution to all the subcellular physiological complications that are observed in AD. Therefore, the aim of this review was to unearth the prospective of CCB against cognitive frailty with a sole purpose of elucidating CCB as cognitive enhancers, which could find its use as a drug in prevention or treatment of AD.

Caveolin-1 is the principal marker of caveolae in endothelial cells. It plays an important role in physiological and pathological conditions of the blood-brain barrier and serves as a mediator in drug delivery through the blood-brain barrier. Caveolin-1 is related to the diminished expression of tight junction-associated proteins and metabolic pinocytosis vesicles when the blood-brain barrier is destroyed by outside invaders or malignant stimulus. The permeability of the blood-brain barrier, regulated by types of drugs or physical irradiation, is connected with drug transportation with the participation of caveolin-1. Caveolin-1, which serves as a platform or medium for signal transduction, cooperates with several signal molecules by forming a complex. Silencing of caveolin-1 and disruption of caveolae can attenuate or remove pathological damage and even engender the opposite effects in the blood-brain barrier. This review considers the role of caveolin-1 in the blood-brain barrier that may have profound implications for central nervous system disease and drug delivery through the blood-brain barrier.

17β-Estradiol (E2), one of female sex hormones, has well-documented neuroprotective effects in a variety of clinical and experimental disorders of the central cerebral ischemia, including stroke and neurodegenerative diseases. The cellular mechanisms that underlie these protective effects of E2 are uncertain because a number of different cell types express estrogen receptors in the central nervous system. Astrocytes are the most abundant cells in the central nervous system and provide structural and nutritive support of neurons. They interact with neurons by cross-talk, both physiologically and pathologically. Proper astrocyte function is particularly important for neuronal survival under ischemic conditions. Dysfunction of astrocytes resulting from ischemia significantly influences the responses of other brain cells to injury. Recent studies demonstrate that estrogen receptors are expressed in astrocytes, indicating that E2 may exert multiple regulatory actions on astrocytes. Cerebral ischemia induced changes in the expression of estrogen receptors in astrocytes. In the present review, we summarize the data in support of possible roles for astrocytes in the mediation of neuroprotection by E2 against cerebral ischemia.

Heme oxygenase (HO) was regarded as an enzyme to degrade heme in aging red blood cells; recent studies suggested HO might have other functions such as neuroprotection. HO degrades heme to produce carbon monoxide (CO), iron (Fe 2+ ) and biliverdin, which is rapidly converted to bilirubin (BR). Three isoforms of HO were identified in the brain: inducible form (HO-1) and constitutive forms (HO-2 and HO-3). HO-1 and HO-2 may have different mechanisms to protect neurons from oxidative stress. HO-1 is normally barely detectable in the brain. HO-1 can be induced mainly in microglia and astrocytes by oxidative stimulus rapidly. HO-1 might function as an emerging molecule to protect neurons against acute insults mediated by facilitating iron efflux from cells under stress conditions. Up-regulation of HO-1 was also found in brain glial cells in the aging and neurodegenerative diseases. This may lead to iron deposition and oxidative mitochondrial injury. HO-1 may confer neuroprotection or neurotoxic effect because of the balance between beneficial and toxic effects of heme and heme products. Pharmacological modulation of HO-1 induction represents a therapeutic strategy for several nervous system disorders. HO-2 predominantly expressed in neurons. Bilirubin has been demonstrated to protect neurons from oxidative stress in vivo and in vitro . Bilirubin can be oxidized to biliverdin by scavenging peroxyl radicals. HO-2 could protect neurons through bilirubin pathway. HO-2 might also promote neuronal survival through the CO-cGMP-MAPK pathway. Biliverdin/bilirubin may be possible therapeutic candidates to treat nervous system disease related with oxidative damage.

Activation of proinflammatory and anti-inflammatory cytokines network seems to have a role in febrile seizures (FS). The present meta-analysis was aimed to pool the inconsistent data provided with case-control studies on the relationship of proinflammatory and anti-inflammatory cytokines and FS/epilepsy risk. The genotype interleukin (IL)-1α-889 1/1 (recessive model) was significantly correlated with increased risk of epilepsy ( p =0.008) and FS/epilepsy ( p =0.004). Patients with IL-1β-511 T/T homozygote were more susceptible to develop FS ( p =0.036) but not epilepsy. Furthermore, the T/T genotype was totally associated with increased risk of FS/epilepsy ( p =0.043). Although the recessive model was also confirmed for the Asian subgroup (FS and FS/epilepsy), we found a protective effect of C/C genotype toward developing FS in the Caucasian race ( p =0.020). The second meta-analysis on cytokine levels showed a statistically higher serum level of IL-6 in patients with epilepsy compared to control subjects without epilepsy. The present meta-analysis showed that two alleles of proinflammatory cytokines (IL-1α-889 and IL-1β-511) in addition to the serum concentration of IL-6 were significantly associated with FS and epilepsy or both in various subgroup analyses.