The immune system (IS) and the central nervous system (CNS) are functionally coupled, and a large number of endogenous molecules (i.e., the chemokines for the IS and the classic neurotransmitters for ...the CNS) are shared in common between the two systems. These interactions are key elements for the elucidation of the pathogenesis of central inflammatory diseases. In recent years, evidence has been provided supporting the role of chemokines as modulators of central neurotransmission. It is the case of the chemokines CCL2 and CXCL12 that control pre- and/or post-synaptically the chemical transmission. This article aims to review the functional cross-talk linking another endogenous pro-inflammatory factor released by glial cells, i.e., the chemokine Regulated upon Activation Normal T-cell Expressed and Secreted (CCL5) and the principal neurotransmitter in CNS (i.e., glutamate) in physiological and pathological conditions. In particular, the review discusses preclinical data concerning the role of CCL5 as a modulator of central glutamatergic transmission in healthy and demyelinating disorders. The CCL5-mediated control of glutamate release at chemical synapses could be relevant either to the onset of psychiatric symptoms that often accompany the development of multiple sclerosis (MS), but also it might indirectly give a rationale for the progression of inflammation and demyelination. The impact of disease-modifying therapies for the cure of MS on the endogenous availability of CCL5 in CNS will be also summarized. We apologize in advance for omission in our coverage of the existing literature.
Synaptosomes are used to decipher the mechanisms involved in chemical transmission, since they permit highlighting the mechanisms of transmitter release and confirming whether the activation of ...presynaptic receptors/enzymes can modulate this event. In the last two decades, important progress in the field came from the observations that synaptosomes retain changes elicited by both "in vivo" and "in vitro"
chemical stimulation. The novelty of these studies is the finding that these adaptations persist beyond the washout of the triggering drug, emerging subsequently as functional modifications of synaptosomal performances, including release efficiency. These findings support the conclusion that synaptosomes are plastic entities that respond dynamically to ambient stimulation, but also that they "learn and memorize" the functional adaptation triggered by
exposure to chemical agents. This work aims at reviewing the results so far available concerning this form of synaptosomal learning, also highlighting the role of these
chemical adaptations in pathological conditions.
Autoantibodies against NMDA and AMPA receptors have been identified in the central nervous system of patients suffering from brain disorders characterized by neurological and psychiatric symptoms. It ...has been demonstrated that these autoantibodies can affect the functions and/or the expression of the targeted receptors, altering synaptic communication. The importance to clarify, in preclinical models, the molecular mechanisms involved in the autoantibody-mediated effects has emerged in order to understand their pathogenic role in central disorders, but also to propose new therapeutic approaches for preventing the deleterious central consequences. In this review, we describe some of the available preclinical literature concerning the impact of antibodies recognizing NMDA and AMPA receptors in neurons. This review discusses the cellular events that would support the detrimental roles of the autoantibodies, also illustrating some contrasting findings that in our opinion deserve attention and further investigations before translating the preclinical observations to clinic.
Somatostatin is widely diffused in the central nervous system, where it participates to control the efficiency of synaptic transmission. This peptide mainly colocalizes with GABA, in inhibitory, ...GABA-containing interneurons from which it is actively released in a Ca
dependent manner upon application of depolarizing stimuli. Once released in the synaptic cleft, somatostatin acts locally, or it diffuses in the extracellular space through "volume diffusion", a mechanism(s) of distribution which mainly operates in the cerebrospinal fluid and that assures the progression of neuronal signalling from signal-secreting sender structures towards receptor-expressing targeted neurons located extrasynaptically, in a non-synaptic, inter-neuronal form of communication. Somatostatin controls the efficiency of central glutamate transmission by either modulating presynaptically the glutamate exocytosis or by metamodulating the activity of glutamate receptors colocalized and functionally coupled with somatostatin receptors in selected subpopulations of nerve terminals. Deciphering the role of somatostatin in the mechanisms of "volume diffusion" and in the "receptor-receptor interaction" unveils new perspectives in the central role of this fine tuner of synaptic strength, paving the road to new therapeutic approaches for the cure of central disorders.
Group I metabotropic glutamate (mGlu) receptors consists of mGlu1 and mGlu5 receptor subtypes. These receptors are widely distributed in the central nervous system (CNS), where they preferentially ...mediate facilitatory signaling in neurones and glial cells, mainly by favoring phospholipase (PLC) translocation. Based on the literature so far available, group I Metabotropic glutamate receptors (mGluRs) are preferentially expressed at the postsynaptic side of chemical synapsis, where they participate in the progression of the chemical stimulus. Studies, however, have shown the presence of these receptors also at the presynaptic level, where they exert several functions, including the modulation of transmitter exocytosis. Presynaptic Group I mGluRs can be both autoreceptors regulating release of glutamate and heteroreceptors regulating the release of various transmitters, including GABA, dopamine, noradrenaline, and acetylcholine. While the existence of presynaptic release-regulating mGlu5 receptors is largely recognized, the possibility that mGlu1 receptors also are present at this level has been a matter of discussion for a long time. A large body of evidence published in the last decade, however, supports this notion. This review aims at revisiting the data from in vitro studies concerning the existence and the role of release-regulating mGlu1 receptors presynaptically located in nerve terminals isolated from selected regions of the CNS. The functional interaction linking mGlu5 and mGlu1 receptor subtypes at nerve terminals and their relative contributions as modulators of central transmission will also be discussed. We apologize in advance for omission in our coverage of the existing literature.
Epigenetic mechanisms are involved in the pathophysiology of depressive disorders and are unique potential targets for therapeutic intervention. The acetylating agent L-acetylcarnitine (LAC), a ...welltolerated drug, behaves as an antidepressant by the epigenetic regulation of type 2 metabotropic glutamate (mGlu2) receptors. It caused a rapid and long-lasting antidepressant effect in Flinders Sensitive Line rats and in mice exposed to chronic unpredictable stress, which, respectively, model genetic and environmentally induced depression. In both models, LAC increased levels of acetylated H3K27 bound to the Grm2 promoter and also increased acetylation of NF-KB-p65 subunit, thereby enhancing the transcription of Grm2 gene encoding for the mGlu2 receptor in hippocampus and prefrontal cortex. Importantly, LAC reduced the immobility time in the forced swim test and increased sucrose preference as early as 3 d of treatment, whereas 14 d of treatment were needed for the antidepressant effect of chlorimipramine. Moreover, there was no tolerance to the action of LAC, and the antidepressant effect was still seen 2 wk after drug withdrawal. Conversely, NF-κB inhibition prevented the increase in mGlu2 expression induced by LAC, whereas the use of a histone deacetylase inhibitor supported the epigenetic control of mGlu2 expression. Finally, LAC had no effect on mGlu2 knockout mice exposed to chronic unpredictable stress, and a single injection of the mGlu2/3 receptor antagonist LY341495 partially blocked LAC action. The rapid and long-lasting antidepressant action of LAC strongly suggests a unique approach to examine the epigenetic hypothesis of depressive disorders in humans, paving the way for more efficient antidepressants with faster onset of action.
The existence of presynaptic, release‐regulating NMDA receptors in the CNS has been long matter of discussion. Most of the reviews dedicated to support this conclusion have preferentially focussed on ...the results from electrophysiological studies, paying little or no attention to the data obtained with purified synaptosomes, even though this experimental approach has been recognized as providing reliable information concerning the presence and the role of presynaptic release‐regulating receptors in the CNS. To fill the gap, this review is dedicated to summarising the results from studies with synaptosomes published during the last 40 years, which support the existence of auto and hetero NMDA receptors controlling the release of transmitters such as glutamate, GABA, dopamine, noradrenaline, 5‐HT, acetylcholine and peptides, in the CNS of mammals. The review also deals with the results from immunochemical studies in isolated nerve endings that confirm the functional observations.
Multiple sclerosis (MS) is an autoimmune inflammatory disease characterized by demyelination, axonal loss, and synaptic impairment in the central nervous system (CNS). The available therapies aim to ...reduce the severity of the pathology during the early inflammatory stages, but they are not effective in the chronic stage of the disease. In this phase, failure in endogenous remyelination is associated with the impairment of oligodendrocytes progenitor cells (OPCs) to migrate and differentiate into mature myelinating oligodendrocytes. Therefore, stimulating differentiation of OPCs into myelinating oligodendrocytes has become one of the main goals of new therapeutic approaches for MS. Different disease-modifying therapies targeting sphingosine-1-phosphate receptors (S1PRs) have been approved or are being developed to treat MS. Besides their immunomodulatory effects, growing evidence suggests that targeting S1PRs modulates mechanisms beyond immunomodulation, such as remyelination. In this context, this review focuses on the current understanding of S1PR modulators and their direct effect on OPCs and oligodendrocytes.
Abnormalities of synaptic transmission in the hippocampus represent an integral part of the altered programming triggered by early life stress, which enhances the vulnerability to stress-related ...disorders in the adult life. Rats exposed to prenatal restraint stress (PRS) develop enduring biochemical and behavioral changes characteristic of an anxious/depressive-like phenotype. Most neurochemical abnormalities in PRS rats are found in the ventral hippocampus, a region that encodes memories related to stress and emotions. We have recently demonstrated a causal link between the reduction of glutamate release in the ventral hippocampus and anxiety-like behavior in PRS rats. To confer pharmacological validity to the glutamatergic hypothesis of stress-related disorders, we examined whether chronic treatment with two antidepressants with different mechanisms of action could correct the defect in glutamate release and associated behavioral abnormalities in PRS rats. Adult unstressed or PRS rats were treated daily with either agomelatine (40 mg/kg, i.p.) or fluoxetine (5 mg/kg, i.p.) for 21 d. Both treatments reversed the reduction in depolarization-evoked glutamate release and in the expression of synaptic vesicle-associated proteins in the ventral hippocampus of PRS rats. Antidepressant treatment also corrected abnormalities in anxiety-/depression-like behavior and social memory performance in PRS rats. The effect on glutamate release was strongly correlated with the improvement of anxiety-like behavior and social memory. These data offer the pharmacological demonstration that glutamatergic hypofunction in the ventral hippocampus lies at the core of the pathological phenotype caused by early life stress and represents an attractive pharmacological target for novel therapeutic strategies.
Metabotropic glutamate (mGlu) receptors represent the largest family of glutamate receptors in mammals and act as fine tuners of the chemical transmission in central nervous system (CNS).
In the last ...decade, results concerning the expression and the subcellular localization of mGlu receptors further clarified their role in physio-pathological conditions. Concomitantly, their pharmacological characterization largely improved thanks to the identification of new compounds (chemical ligands and antibodies recognizing epitopic sequences of the receptor proteins) that allowed to decipher the protein compositions of the naive receptors.
mGlu receptors are expressed at the presynaptic site of chemical synapses. Here, they modulate intraterminal enzymatic pathways controlling the migration and the fusion of vesicles to synaptic membranes as well as the phosphorylation of colocalized receptors. Both the control of transmitter exocytosis and the phosphorylation of colocalized receptors elicited by mGlu receptors are relevant events that dictate the plasticity of nerve terminals, and account for the main role of presynaptic mGlu receptors as modulators of neuronal signalling.
The role of the presynaptic mGlu receptors in the CNS has been the matter of several studies and this review aims at briefly summarizing the recent observations obtained with isolated nerve endings (we refer to as synaptosomes). We focus on the pharmacological characterization of these receptors and on their receptor-receptor interaction / oligo-dimerization in nerve endings that could be relevant to the development of new therapeutic approaches for the cure of central pathologies.
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