Pharmacology of Neurotransmitter Release: 184 (Handbook of Experimental Pharmacology)
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J Neurophysiol 89 : — , doi: Invest Ophthalmol Vis Sci 49 : — , doi: Vis Neurosci 28 : 95 — , doi: Br J Ophthalmol 87 : — , doi: Invest Ophthalmol Vis Sci 45 : — , doi: Hartveit E Reciprocal synaptic interactions between rod bipolar cells and amacrine cells in the rat retina. J Neurophysiol 81 : — , pmid: Hatton GI Synaptic modulation of neuronal coupling.
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J Neurosci 32 : — , doi: Invest Ophthalmol Vis Sci 50 : — , doi: Korenbrot JI Speed, sensitivity, and stability of the light response in rod and cone photoreceptors: facts and models. Prog Retin Eye Res 31 : — , doi: Am J Ophthalmol : — , doi: Invest Ophthalmol Vis Sci 39 : — , pmid: PLoS One 7 : e , doi: Limbird LE Receptors linked to inhibition of adenylate cyclase: additional signaling mechanisms. OpenUrl Abstract. Miller RJ Presynaptic receptors. Annu Rev Pharmacol Toxicol 38 : — , doi: Oesch NW , Diamond JS Ribbon synapses compute temporal contrast and encode luminance in retinal rod bipolar cells.
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Invest Ophthalmol Vis Sci 51 : — , doi: Back to top. Two new, channel-mediated mechanisms of glutamate release from astrocytes were proposed in when Woo et al. Nevertheless, the neuronal inward currents generated from Best 1-mediated glutamate release were much slower than those generated from glutamate exocytosis [ ]. However, TREKmediated glutamate release is very rapid within milliseconds relative to Bestmediated release [ ].
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Activating these receptors in cultured and in situ astrocytes induces ATP uptake and glutamate release simultaneously Figure 2 d [ ]. However, the extent to which these receptors are involved in glutamate release from astrocytes in vivo in healthy conditions remains unknown. It was reported for the first time in that the activation of cystine uptake in cerebellar preparations, induced glutamate release from astrocytes and triggered inward currents in the Purkinje cells [ ].
Later, similar results were obtained in the rat striatum. When researchers blocked cystine uptake transporters, this resulted in a significant decrease in the extracellular glutamate concentration [ ]. Additionally, applying physiological concentrations of cystine, in vivo, to acutely cut brain slices augmented the extracellular glutamate level [ ]. This mechanism occurs, most likely, in pathological conditions only, as blocking glutamate uptake transporters did not influence astrocytic glutamate release in healthy conditions [ , , ].
Connexin and Pannexin proteins that form the gap junctions between astrocytes exist in the form of hemichannels that allow the passage of molecules from the cytoplasm to the extracellular space. This mechanism of glutamate release was reported, in vitro and in vivo, in swollen astrocytes. As in the case of brain edema and stroke, VRACs open and permit glutamate release to the extracellular space Figure 2 h [ , ].
Despite the great efforts that have been done in the last three decades to understand the various mechanisms implicated in astrocytic gliotransmitter release and its significance in the regulation of neuronal activity, it is still an issue of debate whether astrocytes are able to release glutamate, in vivo, under physiological conditions [ 7 , , ].
Many researchers have several arguments against the ability of astrocytes to release glutamate in physiological conditions. First, the concentration of glutamate in astrocytes is very low compared to neurons, due to the high activity of the enzyme, glutamine synthetase, that converts glutamate to glutamine, and therefore, it is unlikely that astrocytes would be able to preserve glutamate and pack it inside vesicles [ ].
Even if they could do so, the concentration of glutamate would be too low to generate these inward currents in the adjacent neurons [ ]. From our point of view, the recent studies provided satisfactory evidence that astrocytes can release glutamate, in vitro and in vivo.
However, many questions remain unanswered, including the principal mechanisms by which astrocytes release glutamate, in vivo, and the contribution of each mechanism of glutamate release to CNS homeostasis under physiological and pathological conditions. How do astrocytes maintain the balance between glutamate uptake and release, and what controls the fate of glutamate in astrocytes? All these questions open the door for researchers to generate more hypotheses for in-depth investigations to uncover the mysterious reality of astroglial glutamate release. Under normal conditions, glutamate in the extracellular space must be maintained at very low concentrations to prevent overexcitation of glutamate receptors in neurons and protect against neuronal excitotoxicity.
Contrariwise, in CNS disorders, all their pathological mechanisms are accompanied by inflammation. Therefore, most of the CNS diseases are associated with either loss of astroglial glutamate uptake or excessive gliotransmitter release that predispose to glutamate excitotoxicity [ 1 ].
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Inhibition of glutamate uptake transporters in astrocytes and, subsequently, impaired glutamate uptake are implicated in the pathogenesis of many CNS pathologies, as in the case of traumatic brain injury, where the expression of both EAAT-1 and EAAT-2 in astrocytes is markedly reduced up to 7 days post-trauma [ ], and the same effect on the expression of glutamate transporters occurs in CNS infection with the human immunodeficiency virus HIV [ ].
Neurodegenerative diseases are also associated with the repression of glutamate uptake [ ]. Patients with amyotrophic lateral sclerosis ALS suffer from a loss of the motor neuronal functions caused by a lack of EAAT-2 expression in spinal cord astrocytes [ ]. In another study on the experimental autoimmune encephalomyelitis EAE, a mouse model of multiple sclerosis , excess extracellular glutamate not only predisposed mice to neuronal death, but also led to degeneration of oligodendrocytes and accelerated demyelination [ ].
In human MS as well, many studies provided evidence that glutamate excitotoxicity is implicated in the pathogenesis of the disease [ , ]. Noteworthy, riluzole, an anti-glutamatergic drug, is now in clinical trials for the treatment of recent onset less than one year multiple sclerosis [ ]. Failure of astrocytes to uptake glutamate is a common feature in CNS disorders associated with depletion or reversal of the driving forces of glutamate uptake. In addition to uptake failure, reversal of uptake transporters may occur in these conditions, leading to excessive release of glutamate, which worsens glutamate excitotoxicity.
In the same regard, recent studies in the field of neuro-psychiatry proposed that combined dysregulation of both astroglial glutamate uptake and release potentially contributes to the development of mood disorders and depression-like symptoms in animal models, as well as major depressive disorder MDD and schizophrenia in humans [ , , ].
Interestingly, riluzole also mediates an anti-depressant effect in patients with MDD [ , ].
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Glutamate excitotoxicity is the process by which neuronal death, by apoptosis or necrosis, occurs as a result of excessive or prolonged exposure of neurons to the extracellular glutamate [ 5 ]. Different mechanisms interact synergistically and result, eventually, in neuronal death extensively reviewed by Dong et al. Therefore, we summarize the key molecular and cellular mechanisms involved in this process Figure 3. Noteworthy, this mechanism commonly induces acute rather than a chronic type of excitotoxic neuronal damage [ ].
Oxidative stress, in turn, causes damage to the intracellular proteins, lipids, and nucleic acid, which activates the intracellular apoptotic pathways [ ]. Since their discovery, astrocytes were considered as resting cells that fill the space in the CNS, supporting neurons and the BBB.
However, recent discoveries on astrocytes motivated researchers to pay more attention to these cells and the vital role they play in modulating neuronal firing, synaptic transmission, and maintaining the homeostasis of the CNS. Instead of looking at astrocytes as passive responders to different CNS pathologies, now, we believe that they are actively implicated in the initiation and progression of many, if not all, CNS diseases.
Knowing the unique role of astrocytes in maintaining glutamate homeostasis and regulating the balance between glutamate uptake and release in the CNS would help us to understand better the mechanisms of the CNS disorders in which glutamate excitotoxicity is involved. It also opens the door for investigators to consider astrocytes as a therapeutic target for these disorders. In this regard, appreciative efforts have already been successful in the field of ALS. A promising astrocyte cell-based therapy, using astrocytes derived from embryonic stem cells, is now in clinical trials following its successful application in the SOD1 G93A mouse model of ALS [ , ].
Author Contributions S. All authors have read and approved the manuscript. Many thanks to the granting institutions that support this work.
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We appreciate the continuous support provided by all Gris lab members and their valuable comments on the manuscript. Figure 1. Figure 2. Figure 3. Postsynaptic receptors have received considerable attention as drug targets, but some of the most successful agents influence presynaptic processes, in particular neurotransmitter reuptake. The pharmacological potential of many other presynaptic elements, and in particular the machinery responsible for loading transmitter into vesicles, has received only limited attention. The similarity of vesicular transporters to bacterial drug resistance proteins and the increasing evidence for regulation of vesicle filling and recycling suggest that the pharmacological potential of vesicular transporters has been underestimated.
In this review, we discuss the pharmacological effects of psychostimulants and therapeutic agents on transmitter release.
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