In the central nervous system (CNS), glutamate and gamma-aminobutyric acid (GABA) are major excitatory and inhibitory neurotransmitters respectively. Balance between glutamate and GABA actions is critical for proper CNS function. Excessive glutamate accumulation has been associated with neuronal damage in a myriad of neurological and neuropsychiatric disorders including epilepsy, stroke, amyotrophic lateral sclerosis and others. We hypothesize that the CNS may have endogenous mechanisms by which glutamate release is selectively dampened, thereby maintaining or resetting the balance between excitation and inhibition during excessive activity. Novel ameliorative strategies might arise from better understanding and exploiting endogenous mechanisms that the nervous system itself uses to restore balance between excitation and inhibition. We explore two homeostatic mechanisms that, at the level of presynaptic vesicle release, depress glutamate release selectively over GABA release. The first synaptic adaptation is an acute change in vesicle release probability at glutamate but not GABA synapses. Glutamate synapses possess more """"""""reluctant vesicles"""""""" than GABA synapses, identifiable with short trains of action potentials that fail to release otherwise accessible vesicles. Reluctant vesicles may be present at a distinct set of presynaptic terminals from willing vesicles or may arise within terminals as a result of stimulus-dependent factors. We propose to study the mechanisms and regulation of reluctant vesicles. We hypothesize a rapid-onset, calcium-dependent feedback mechanism is particularly important in vesicle reluctance. The second synaptic adaptation is a persistent change in glutamate vesicle availability that outlives the inducing stimulus. We show that normal action potential activity suffices to inactivate a small percentage of glutamate vesicles, and that the number of inactivated vesicles is increased by augmenting neuronal activity. We hypothesize that the persistent changes differ mechanistically from other more commonly studied forms of persistent synaptic plasticity and that the changes are induced by local presynaptic calcium influx, which alters the number of functionally active presynaptic terminals. By better understanding the modulation of vesicle release probability and availability, we may learn to exploit the mechanisms for clinical benefit in disorders of excitotoxicity, and we will broaden our understanding of the reliability and malleability of glutamate synapses. ? ?
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