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

J Neurosci. 2011 Sep 21;31(38):13546-61. doi: 10.1523/JNEUROSCI.2781-11.2011.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials / physiology
  • Animals
  • CA1 Region, Hippocampal / metabolism
  • CA1 Region, Hippocampal / physiology
  • Calcium / metabolism*
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels, T-Type / metabolism
  • Calcium Channels, T-Type / physiology*
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / physiology
  • Choline O-Acetyltransferase / genetics
  • In Vitro Techniques
  • Interneurons / metabolism*
  • Interneurons / physiology
  • Interneurons / ultrastructure
  • Mice
  • Mice, Transgenic
  • Microinjections
  • Nerve Endings / physiology*
  • Nerve Endings / ultrastructure
  • Nicotinic Agonists / administration & dosage
  • Nicotinic Agonists / pharmacology
  • Nicotinic Antagonists / administration & dosage
  • Nicotinic Antagonists / pharmacology
  • Patch-Clamp Techniques
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Nicotinic / physiology*
  • Synaptic Transmission / physiology*
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • Calcium Channel Blockers
  • Calcium Channels, T-Type
  • Nicotinic Agonists
  • Nicotinic Antagonists
  • Receptors, Nicotinic
  • gamma-Aminobutyric Acid
  • Choline O-Acetyltransferase
  • Calcium