title: Nerve terminal nicotinic acetylcholine receptors initiate quantal GABA release from perisomatic interneurons by activating axonal T-type (Cav3) Ca²⁺ channels and Ca²⁺ release from stores.
abstract: Release of conventional neurotransmitters is mainly controlled by calcium (Ca²⁺) influx via high-voltage-activated (HVA), Ca(v)2, 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(v)3 ("T-type"), channels take part. GABA release from cortical perisomatic-targeting interneurons affects numerous physiological processes, and yet its underlying control mechanisms are not fully understood. We investigated whether T-type Ca²⁺ 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 electron-microscopy, and optogenetic methods. We show that Ca(v)3.1, T-type Ca²⁺ 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 Ca²⁺ influx through presynaptic T-type Ca²⁺ channels, augmented by Ca²⁺ from internal stores, following focal microiontophoretic activation of the α3β4 nAChRs. The resulting GABA release can inhibit pyramidal cells. The T-type Ca²⁺ channel-dependent mechanism is not dependent on, or accompanied by, HVA channel Ca²⁺ influx, and is insensitive to agonists of cannabinoid, μ-opioid, or GABA(B) receptors. It may therefore 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.
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Ai-Hui
authors.initials: AH
authors.lastname: Tang
authors.forename: Miranda A
authors.initials: MA
authors.lastname: Karson
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Nagode
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.forename: Victor N
authors.initials: VN
authors.lastname: Uebele
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.forename: Matthias
authors.initials: M
authors.lastname: Klugmann
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Milner
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Alger
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020747:Calcium Channels, T-Type / Q000378:metabolism / Q000502:physiology*; D002540:Cerebral Cortex / Q000378:metabolism / Q000502:physiology; D002795:Choline O-Acetyltransferase / Q000235:genetics; D066298:In Vitro Techniques; D007395:Interneurons / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D051379:Mice; D008822:Mice, Transgenic; D008845:Microinjections; D009411:Nerve Endings / Q000502:physiology* / Q000648:ultrastructure; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D005680:gamma-Aminobutyric Acid; D002795:Choline O-Acetyltransferase; D002118:Calcium