Selective Depression of Low–Release Probability Excitatory Synapses by Sodium Channel Blockers

Abstract

Sodium channels (NaChs) play a central role in action potential generation and are uniquely poised to influence the efficacy of transmitter release. We evaluated the effect of partial NaCh blockade on two aspects of synaptic efficacy First, we evaluated whether NaCh blockade accounts for the ability of certain drugs to selectively depress glutamate release. Second, we evaluated the contribution of NaChs to intraneuronal variability in glutamate release probability (p(r)). The antiglutamate drug riluzole nearly completely depresses glutamate excitatory postsynaptic currents (EPSCs) at concentrations that barely affect GABAergic inhibitory postsynaptic currents (IPSCs). NaCh inhibition explains the selective depression. Unlike other presynaptic depressants, partial NaCh blockade increases paired-pulse EPSC depression. This result is explained by selective depression of low-p(r) synapses. We conclude that local variations in the action potential contribute to p(r) variability among excitatory synapses.

Loss of Local Astrocyte Support Disrupts Action Potential Propagation and Glutamate Release Synchrony from Unmyelinated Hippocampal Axon Terminals In Vitro

“…We found that evoked GABAergic IPSCs displayed no waveform differences when grown on either ϩastrocyte or Ϫas-trocyte microcultures ( Fig. 2A, gray bars) and were indistinguishable from IPSCs from previous work (Bekkers and Stevens, 1991;Mennerick and Zorumski, 1995;Prakriya and Mennerick, 2000;Vecchia et al, 2014).…”

Rapid Enhancement of Glutamatergic Neurotransmission in Bipolar Depression Following Treatment with Riluzole

“…The marked increase in the Gln/Glu ratio at day 2 of riluzole treatment was unexpected, given previous in vitro findings that riluzole decreases presynaptic glutamate release (Doble et al, 1992;Martin et al, 1993;Prakriya and Mennerick, 2000;Wang et al, 2004). However, animal studies provide some support for our finding.…”

Short-Term Presynaptic Plasticity

“…An alteration in the firing threshold for somatic or extracellular activation that involves the Na/K-ATPase could contribute to short-term depression at these synapses (Munoz-Cuevas et al 2004). A failure of an action potential to invade some axonal branches may contribute to depression in cultured hippocampal cells (Brody and Yue 2000;Prakriya and Mennerick 2000), but action potential invasion of axons is generally reliable in more intact tissue (Cox et al 2000;Kreitzer and Regehr 2001;Brenowitz and Regehr 2007).…”