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

• Published in: The Journal of physiology 2011-07, Vol.589 (13), p.3211-3229
• Main Authors: El‐Hassar, Lynda, Hagenston, Anna M., D’Angelo, Lisa Bertetto, Yeckel, Mark F.
• Format: Article
• Language: English
• Subjects: Action Potentials - physiology; Animals; Brain slice preparation; CA1 Region, Hippocampal - physiology; Calcium; Calcium (intracellular); Calcium channels; Calcium imaging; Calcium Signaling - physiology; Calcium signalling; Cognitive ability; Cyclic AMP; Excitability; Glutamic acid receptors; Glutamic acid receptors (metabotropic); Hippocampus; Hyperpolarization; Information processing; Male; Memory; Neurons; Neurons - physiology; Neuroscience; Neurotransmitters; Pyramidal cells; Pyramidal Cells - physiology; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate - physiology; Small-Conductance Calcium-Activated Potassium Channels - physiology; transient receptor potential proteins; TRPC Cation Channels - physiology
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2011.209783

Non‐technical summary  The hippocampus is a neural structure that is critical for some forms of memory function. It performs this function through the ability of its neurons to fire patterns of activity that encode information and the ability of the synaptic connections between neurons to strengthen or weaken. Glutamate, an important synaptic neurotransmitter, can activate different types of receptors, including metabotropic glutamate receptors (mGluRs). mGluRs have been shown to be important for learning and memory. It has also been shown that changes in mGluR type 5 might contribute to mental retardation and autism, suggesting that manipulation of mGluR5 might reduce their symptoms. In this study we examined how mGluR activation can activate neuron membrane channels (SK and TRPC) in hippocampal neurons that regulate their activity. Our findings suggest that mGluR activation of SK and TRPC channels are likely to be important for sculpting patterns of activity that encode information by the hippocampus.   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+