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Two Forms of Synaptic Depression Produced by Differential Neuromodulation of Presynaptic Calcium Channels.

ABSTRACT: Neuromodulators are important regulators of synaptic transmission throughout the brain. At the presynaptic terminal, neuromodulation of calcium channels (CaVs) can affect transmission not only by changing neurotransmitter release probability, but also by shaping short-term plasticity (STP). Indeed, changes in STP are often considered a requirement for defining a presynaptic site of action. Nevertheless, some synapses exhibit non-canonical forms of neuromodulation, where release probability is altered without a corresponding change in STP. Here, we identify biophysical mechanisms whereby both canonical and non-canonical presynaptic neuromodulation can occur at the same synapse. At a subset of glutamatergic terminals in prefrontal cortex, GABA_B and D1/D5 dopamine receptors suppress release probability with and without canonical increases in short-term facilitation by modulating different aspects of presynaptic CaV function. These findings establish a framework whereby signaling from multiple neuromodulators can converge on presynaptic CaVs to differentially tune release dynamics at the same synapse.

SUBMITTER: Burke KJ

PROVIDER: S-EPMC7874512 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Two Forms of Synaptic Depression Produced by Differential Neuromodulation of Presynaptic Calcium Channels.

Burke Kenneth J KJ Keeshen Caroline M CM Bender Kevin J KJ

Neuron 20180816 5

Neuromodulators are important regulators of synaptic transmission throughout the brain. At the presynaptic terminal, neuromodulation of calcium channels (CaVs) can affect transmission not only by changing neurotransmitter release probability, but also by shaping short-term plasticity (STP). Indeed, changes in STP are often considered a requirement for defining a presynaptic site of action. Nevertheless, some synapses exhibit non-canonical forms of neuromodulation, where release probability is al ...[more]

PMID: 30122380

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Project description:Synapses and circuits rely on homeostatic forms of regulation in order to transmit meaningful information. The Drosophila melanogaster neuromuscular junction (NMJ) is a well-studied synapse that shows robust homeostatic control of function. Most prior studies of homeostatic plasticity at the NMJ have centered on presynaptic homeostatic potentiation (PHP). PHP happens when postsynaptic muscle neurotransmitter receptors are impaired, triggering retrograde signaling that causes an increase in presynaptic neurotransmitter release. As a result, normal levels of evoked excitation are maintained. The counterpart to PHP at the NMJ is presynaptic homeostatic depression (PHD). Overexpression of the Drosophila vesicular glutamate transporter (VGlut) causes an increase in the amplitude of spontaneous events. PHD happens when the synapse responds to the challenge by decreasing quantal content (QC) during evoked neurotransmissionagain, resulting in normal levels of postsynaptic excitation. We hypothesized that there may exist a class of molecules that affects both PHP and PHD. Impairment of any such molecule could hurt a synapses ability to respond to any significant homeostatic challenge. We conducted an electrophysiology-based screen for blocks of PHD. We did not observe a block of PHD in the genetic conditions screened, but we found loss-of-function conditions that led to a substantial deficit in evoked amplitude when combined with VGlut overexpression. The conditions causing this phenotype included a double heterozygous loss-of-function condition for genes encoding the inositol trisphosphate receptor (IP3R itpr) and ryanodine receptor (RyR). IP3Rs and RyRs gate calcium release from intracellular stores. Pharmacological agents targeting IP3R and RyR recapitulated the genetic losses of these factors, as did lowering calcium levels from other sources. Our data are consistent with the idea that the homeostatic signaling process underlying PHD is especially sensitive to levels of calcium at the presynapse.

Dataset Information

Two Forms of Synaptic Depression Produced by Differential Neuromodulation of Presynaptic Calcium Channels.

Publications

Two Forms of Synaptic Depression Produced by Differential Neuromodulation of Presynaptic Calcium Channels.

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