Nerve terminal nicotinic acetylcholine receptors initiate quantal GABA release from perisomatic interneurons by activating axonal t-type (ca v3) ca 2+ channels and ca 2+ release from stores

Abstract

Release of conventional neurotransmitters is mainly controlled by calcium (Ca 2+) influx via high-voltage-activated (HVA), Ca v2, channels ("N-, P/Q-, or R-types") that are opened by action potentials. Regulation of transmission by subthreshold depolarizations does occur, but there is little evidence that low-voltage-activated, Ca v3 ("T-type"), channels take part. GABA release from cortical perisomatictargeting interneurons affects numerous physiological processes, and yet its underlying control mechanisms are not fully understood. We investigated whether T-type Ca 2+ channels are involved in regulating GABA transmission from these cells in rat hippocampal CA1 using a combination of whole-cell voltage-clamp, multiple-fluorescence confocal microscopy, dual-immunolabeling electronmicroscopy, and optogenetic methods. We show that Ca v3.1, T-type Ca 2+ channels can be activated by α3β4 nicotinic acetylcholine receptors (nAChRs) that are located on the synaptic regions of the GABAergic perisomatic-targeting interneuronal axons, including the parvalbumin-expressing cells. Asynchronous, quantal GABA release can be triggered by Ca 2+ influx through presynaptic T-type Ca 2+ channels, augmented by Ca 2+ from internal stores, following focal microiontophoretic activation of the α3β4 nAChRs. The resulting GABArelease can inhibit pyramidal cells. The T-type Ca 2+channel-dependent mechanism is not dependent on, or accompanied by,HVA channel Ca 2+ influx, and is insensitive to agonists of cannabinoid,μ-opioid, or GABA B receptors. Itmaytherefore operate in parallel with the normal HVA-dependent processes. The results reveal new aspects of the regulation of GABA transmission and contribute to a deeper understanding of ACh and nicotine actions in CNS. © 2011 the authors.