Cholinergic suppression of KCNQ channel currents enhances excitability of striatal medium spiny neurons

  • Shen W
  • Hamilton S
  • Nathanson N
 et al. 
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Abstract

In response to glutamatergic synaptic drive, striatal medium spiny neurons in vivo transition to a depolarized "up state" near spike threshold. In the up state, medium spiny neurons either depolarize enough to spike or remain below spike threshold and are silent before returning to the hyperpolarized "down state." Previous work has suggested that subthreshold K+ channel currents were responsible for this dichotomous behavior, but the channels giving rise to the current and the factors determining its engagement have been a mystery. To move toward resolution of these questions, perforated-patch recordings from medium spiny neurons in tissue slices were performed. K+ channels with pharmacological and kinetic features of KCNQ channels potently regulated spiking at up-state potentials. Single-cell reverse transcriptase-PCR confirmed the expression of KCNQ2, KCNQ3, and KCNQ5 mRNAs in medium spiny neurons. KCNQ channel currents in these cells were potently reduced by M1 muscarinic receptors, because the effects of carbachol were blocked by M1 receptor antagonists and lost in neurons lacking M1 receptors. Reversal of the modulation was blocked by a phosphoinositol 4-kinase inhibitor, indicating a requirement for phosphotidylinositol 4,5-bisphosphate resynthesis for recovery. Inhibition of protein kinase C reduced the efficacy of the muscarinic modulation. Finally, acceleration of cholinergic interneuron spiking with 4-aminopyridine mimicked the effects of exogenous agonist application. Together, these results show that KCNQ channels are potent regulators of the excitability of medium spiny neurons at up-state potentials, and they are modulated by intrastriatal cholinergic interneurons, providing a mechanistic explanation for variability in spiking during up states seen in vivo.

Author-supplied keywords

  • 4-Aminopyridine/pharmacology
  • Animals
  • Corpus Striatum/cytology/metabolism/physiology
  • Electric Conductivity
  • Electrophysiology
  • Female
  • In Vitro Techniques
  • Interneurons/physiology
  • Ion Channel Gating/physiology
  • KCNQ Potassium Channels/antagonists & inhibitors/g
  • KCNQ2 Potassium Channel/metabolism
  • KCNQ3 Potassium Channel/metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Neurons/metabolism/physiology
  • Phosphatidylinositol 4,5-Diphosphate/physiology
  • Potassium Channel Blockers/pharmacology
  • Protein Kinase C/antagonists & inhibitors/metaboli
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Muscarinic M1/agonists/physiology

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Authors

  • W Shen

  • S E Hamilton

  • N M Nathanson

  • D J Surmeier

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