Heterogeneity and Specificity of Presynaptic Ca2+ Current Modulation by mGluRs at Individual Hippocampal Synapses

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GABA release from axonal boutons formed by cortical interneurons shows target cell-dependent sensitivity to group III metabotropic glutamate receptor (mGluR) agonists, as well as variable dependence on presynaptic Ca2+ influx via N- and P-type channels. How Ca2+ channels interact with heterogeneous mGluR modulation to determine information flow in the synaptic circuitry is not known. Here we combine electrophysiology with two-photon microscopy to analyze Ca2+ influx at individual axonal varicosities of hippocampal interneurons. Action potentials triggered Ca2+ influx at individual varicosities, principally (>80%) via N- and P-type channels. Although Ca2+ influx at some varicosities was almost entirely mediated by N-type channels, P-type channels only contributed up to 60% of the action potential-evoked Ca2+ transient. At a subset of synapses activation of group III mGluRs depressed GABA release, and decreased Ca2+ influx via N-type channels (in contrast to an action on P-type channels reported at auditory brainstem calyceal synapses). The identity of the dominant channel subtype mediating Ca2+ influx tended to be conserved at varicosities supplied by the same axon. In contrast, neighboring varicosities often showed heterogeneous sensitivity to group III mGluR activation. Glutamatergic modulation of GABA release from individual synapses thus depends on the co-occurrence of presynaptic N-type Ca2+ channels and the target cell-dependent expression of group III mGluRs.

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