title: Metabotropic glutamate receptors regulate hippocampal CA1 pyramidal neuron excitability via Ca²⁺ wave-dependent activation of SK and TRPC channels.
abstract: 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.
authors.affiliation: Department of Neurobiology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Lynda
authors.initials: L
authors.lastname: El-Hassar
authors.forename: Anna M
authors.initials: AM
authors.lastname: Hagenston
authors.forename: Lisa Bertetto
authors.initials: LB
authors.lastname: D'Angelo
authors.forename: Mark F
authors.initials: MF
authors.lastname: Yeckel
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D008297:Male; D009474:Neurons / Q000502:physiology*; D017966:Pyramidal Cells / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000502:physiology*; D050052:TRPC Cation Channels / Q000502:physiology*
chemical_list: D018094:Receptors, Metabotropic Glutamate; D051640:Small-Conductance Calcium-Activated Potassium Channels; D050052:TRPC Cation Channels; C104077:metabotropic glutamate receptor type 1