Metabotropic glutamate receptors regulate hippocampal CA1 pyramidal neuron excitability via Ca²⁺ wave-dependent activation of SK and TRPC channels

J Physiol. 2011 Jul 1;589(Pt 13):3211-29. doi: 10.1113/jphysiol.2011.209783. Epub 2011 May 16.


Group I metabotropic glutamate receptors (mGluRs) play an essential role in cognitive function. Their activation results in a wide array of cellular and molecular responses that are mediated by multiple signalling cascades. In this study, we focused on Group I mGluR activation of IP3R-mediated intracellular Ca2+ waves and their role in activating Ca2+-dependent ion channels in CA1 pyramidal neurons. Using whole-cell patch-clamp recordings and high-speed Ca2+ fluorescence imaging in acute hippocampal brain slices, we show that synaptic and pharmacological stimulation of mGluRs triggers intracellular Ca2+ waves and a biphasic electrical response composed of a transient Ca2+-dependent SK channel-mediated hyperpolarization and a TRPC-mediated sustained depolarization. The generation and magnitude of the SK channel-mediated hyperpolarization depended solely on the rise in intracellular Ca2+ concentration ([Ca2+]i), whereas the TRPC channel-mediated depolarization required both a small rise in [Ca2+]i and mGluR activation. Furthermore, the TRPC-mediated current was suppressed by forskolin-induced rises in cAMP. We also show that SK- and TRPC-mediated currents robustly modulate pyramidal neuron excitability by decreasing and increasing their firing frequency, respectively. These findings provide additional evidence that mGluR-mediated synaptic transmission makes an important contribution to regulating the output of hippocampal neurons through intracellular Ca2+ wave activation of SK and TRPC channels. cAMP provides an additional level of regulation by modulating TRPC-mediated sustained depolarization that we propose to be important for stabilizing periods of sustained firing.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology
  • Animals
  • CA1 Region, Hippocampal / physiology*
  • Calcium Signaling / physiology*
  • Male
  • Neurons / physiology*
  • Pyramidal Cells / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Metabotropic Glutamate / physiology*
  • Small-Conductance Calcium-Activated Potassium Channels / physiology*
  • TRPC Cation Channels / physiology*


  • Receptors, Metabotropic Glutamate
  • Small-Conductance Calcium-Activated Potassium Channels
  • TRPC Cation Channels
  • metabotropic glutamate receptor type 1