Distinct Actions of Voltage-Activated Ca2+Channel Block on Spontaneous Release at Excitatory and Inhibitory Central Synapses.
At chemical synapses, voltage-activated calcium channels (VACCs) mediate Ca2+influx to trigger action potential-evoked neurotransmitter release. However, the mechanisms by which Ca2+regulates spontaneous transmission have not been fully determined. We have shown that VACCs are a major trigger of spontaneous release at neocortical inhibitory synapses but not at excitatory synapses, suggesting fundamental differences in spontaneous neurotransmission at GABAergic and glutamatergic synapses. Recently, VACC blockers were reported to reduce spontaneous release of glutamate and it was proposed that there was conservation of underlying mechanisms of neurotransmission at excitatory and inhibitory synapses. Furthermore, it was hypothesized that the different effects on excitatory and inhibitory synapses may have resulted from off-target actions of Cd2+, a nonselective VACC blocker, or other variations in experimental conditions. Here we report that in mouse neocortical neurons, selective and nonselective VACC blockers inhibit spontaneous release at inhibitory but not at excitatory terminals, and that this pattern is observed in culture and slice preparations as well as in synapses from acute slices of the auditory brainstem. The voltage dependence of Cd2+block of VACCs accounts for the apparent lower potency of Cd2+on spontaneous release of GABA than on VACC current amplitudes. Our findings indicate fundamental differences in the regulation of spontaneous release at inhibitory and excitatory synapses by stochastic VACC activity that extend beyond the cortex to the brainstem.SIGNIFICANCE STATEMENTPresynaptic Ca2+entry via voltage-activated calcium channels (VACCs) is the major trigger of action potential-evoked synaptic release. However, the role of VACCs in the regulation of spontaneous neurotransmitter release (in the absence of a synchronizing action potential) remains controversial. We show that spontaneous release is affected differently by VACCs at excitatory and inhibitory synapses. At inhibitory synapses, stochastic openings of VACCs trigger the majority of spontaneous release, whereas they do not affect spontaneous release at excitatory synapses. We find this pattern to be wide ranging, holding for large and small synapses in the neocortex and brainstem. These findings indicate fundamental differences of the Ca2+dependence of spontaneous release at excitatory and inhibitory synapses and heterogeneity of the mechanisms of release across the CNS.
Division of Pulmonary and Critical Care Medicine, Department of Medicine and.|Section of Pulmonary and Critical Care Medicine, VA Portland Health Care System, Portland, Oregon 97239.
Timur
0000-0002-0333-401X
T
Tsintsadze
Division of Pulmonary and Critical Care Medicine, Department of Medicine and.|Section of Pulmonary and Critical Care Medicine, VA Portland Health Care System, Portland, Oregon 97239.
Courtney L
0000-0003-0465-1479
CL
Williams
Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239, and.
Dennis J
DJ
Weingarten
Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239, and.
Henrique
0000-0002-4404-3307
H
von Gersdorff
Division of Pulmonary and Critical Care Medicine, Department of Medicine and smisteph@ohsu.edu.|Section of Pulmonary and Critical Care Medicine, VA Portland Health Care System, Portland, Oregon 97239.
Stephen M
0000-0002-0331-7615
SM
Smith
D000818:Animals; D001933:Brain Stem / Q000166:cytology; D002104:Cadmium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism*; D002478:Cells, Cultured; D019706:Excitatory Postsynaptic Potentials; D005260:Female; D053444:Inhibitory Postsynaptic Potentials; D008297:Male; D051379:Mice; D055369:Miniature Postsynaptic Potentials; D019579:Neocortex / Q000166:cytology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002104:Cadmium
VGCC; calcium channel; mEPSC; mIPSC; minis; spontaneous