Involvement of TRPC4 and 5 Channels in Persistent Firing in Hippocampal CA1 Pyramidal Cells

Cells. 2020 Feb 5;9(2):365. doi: 10.3390/cells9020365.


Persistent neural activity has been observed in vivo during working memory tasks, and supports short-term (up to tens of seconds) retention of information. While synaptic and intrinsic cellular mechanisms of persistent firing have been proposed, underlying cellular mechanisms are not yet fully understood. In vitro experiments have shown that individual neurons in the hippocampus and other working memory related areas support persistent firing through intrinsic cellular mechanisms that involve the transient receptor potential canonical (TRPC) channels. Recent behavioral studies demonstrating the involvement of TRPC channels on working memory make the hypothesis that TRPC driven persistent firing supports working memory a very attractive one. However, this view has been challenged by recent findings that persistent firing in vitro is unchanged in TRPC knock out (KO) mice. To assess the involvement of TRPC channels further, we tested novel and highly specific TRPC channel blockers in cholinergically induced persistent firing in mice CA1 pyramidal cells for the first time. The application of the TRPC4 blocker ML204, TRPC5 blocker clemizole hydrochloride, and TRPC4 and 5 blocker Pico145, all significantly inhibited persistent firing. In addition, intracellular application of TRPC4 and TRPC5 antibodies significantly reduced persistent firing. Taken together these results indicate that TRPC4 and 5 channels support persistent firing in CA1 pyramidal neurons. Finally, we discuss possible scenarios causing these controversial observations on the role of TRPC channels in persistent firing.

Keywords: TRPC antagonists; TRPC channels; cholinergic modulation; hippocampus; intrinsic persistent activity; patch clamp; working memory.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology*
  • Animals
  • Antibodies / pharmacology
  • Benzimidazoles / pharmacology
  • CA1 Region, Hippocampal / drug effects
  • CA1 Region, Hippocampal / physiology*
  • Cholinergic Agonists / pharmacology
  • Indoles / pharmacology
  • Male
  • Mice
  • Neurons / drug effects
  • Neurons / physiology
  • Piperidines / pharmacology
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / physiology*
  • TRPC Cation Channels / antagonists & inhibitors
  • TRPC Cation Channels / metabolism*


  • Antibodies
  • Benzimidazoles
  • Cholinergic Agonists
  • Indoles
  • ML 204
  • Piperidines
  • TRPC Cation Channels
  • TRPC4 ion channel
  • Trpc5 protein, mouse
  • clemizole