Abstract
Synaptic transmission is initiated via spontaneous or action-potential evoked fusion of synaptic vesicles. At excitatory synapses, glutamatergic receptors activated by spontaneous and evoked neurotransmission are segregated. Although inhibitory synapses also transmit signals spontaneously or in response to action potentials, they differ from excitatory synapses in both structure and function. Therefore, we hypothesized that inhibitory synapses may have different organizing principles. We report picrotoxin, a GABAAR antagonist, blocks neurotransmission in a use-dependent manner at rat hippocampal synapses and therefore can be used to interrogate synaptic properties. Using this tool, we uncovered partial segregation of inhibitory spontaneous and evoked neurotransmission. We found up to 40% of the evoked response is mediated through GABAARs which are only activated by evoked neurotransmission. These data indicate GABAergic spontaneous and evoked neurotransmission processes are partially non-overlapping, suggesting they may serve divergent roles in neuronal signaling.
Highlights
Synaptic neuronal communication can be broadly classified into either evoked or spontaneous neurotransmission
We first tested whether PTX acts as a use-dependent g-aminobutyric acid-A receptor (GABAAR) antagonist to selectively block open GABAARs activated during inhibitory neurotransmission in dissociated hippocampal cultures
Under the same conditions, stimulating hippocampal synapses at a variety of frequencies and measuring the evoked IPSC peak amplitudes in the presence of PTX resulted in a response that decreased as a function of stimulation number regardless of PTX incubation time, indicating PTX is a use-dependent antagonist (Figure 1E)
Summary
Synaptic neuronal communication can be broadly classified into either evoked or spontaneous neurotransmission. Synaptic N-methyl-D-aspartate (NMDA) receptors in the hippocampus show a near complete segregation in their responses to spontaneous and evoked glutamate release (Atasoy et al, 2008; Reese and Kavalali, 2016). These studies have demonstrated that spontaneous and evoked neurotransmission can occur at the same synapse; these different forms of transmission activate separate NMDA and AMPA receptors. Segregation may be necessary due to the clear and distinct differences in downstream signaling between evoked and spontaneous neurotransmission at excitatory synapses
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