Regulation of dopamine quantal size in midbrain and hippocampal neurons

Abstract

Since the pioneering work of Bernard Katz and his colleagues decades ago, neurotransmitter quantal size (defined as the number of neurotransmitter molecules released by a single synaptic vesicle during exocytosis) is often modeled as invariant. This assumption had tremendous implications for basic research on synaptic plasticity. For instance, it focused attention on the postsynaptic rather than the presynaptic component in studies of learning and memory (the field of long-term potentiation comes to mind as the best example). Furthermore, this assumption somehow ‘spilled over’ onto studies of monoamine neurotransmitters, which apparently use diffusion and slow action to exert their modulatory effects, in contrast to the fast acting neurotransmitters studied by Katz. Consequently, research on dopamine-related diseases (e.g. psychotic and movement disorders) did not pay as much attention to presynaptic mechanisms that regulate dopamine release, as to postsynaptic receptor action. Part of the problem, of course, has been the lack of technology to directly measure quanta from presynaptic sites and the obligatory reliance on measurements of miniature postsynaptic potentials (minis) for reaching conclusions about presynaptic quantal events. Due to the introduction of the carbon fiber amperometric microelectrode in tissue electrophysiology, initially by Francois Gonon (University of Bordeaux) and then by Mark Wightman (University of North Carolina), we were able to directly measure dopamine quanta from neurites of cultured midbrain dopamine neurons by amperometry. This was the first approach to provide direct measurement of the number of molecules and kinetics of presynaptic quantal release from CNS neuronal terminals. The interventions altering dopamine quantal size are so far the following. (1) Alteration of neurotransmitter synthesis—an increase of cytosolic dopamine availability (e.g. by exposure to l-DOPA) increases quantal size and a decrease of cytosolic dopamine by D2 autoreceptor activation (by quinpirole) decreases quantal size. (2) Modulation of vesicle transmitter transporter activity—overexpression of the neuronal vesicular monoamine transporter VMAT2 increases dopamine quantal size. The reduction or elimination of VMAT2 protein in mice significantly hampers or eliminates monoamine release. (3) Reuptake blockade—cocaine and amfonelic acid are dopamine reuptake blockers which reduce quantal size independently of D2-related effects. (4) Changes in transvesicular pH gradient—neuronal stimulation apparently leads to vesicular acidification via the activation of chloride channels on the vesicular membrane and increased quantal size. (5) Fusion pore kinetics—a vesicle undergoing exocytosis may discharge only part of its neurotransmitter content before recycling. Plasticity of the fusion pore shape may, therefore, be a crucial determinant of quantal size. Other possible sources of variability in quantal size are altered transmitter degranulation and changes in synaptic vesicle volume. We suggest that plasticity in dopamine quantal seems likely to be involved in both normal synaptic modification and disease states.