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5GABA_A Receptors Regulate the Intrinsic Excitability of Mouse Hippocampal Pyramidal Neurons

¹Department of Physiology and ²Institute of Medical Science, University of Toronto; and ³Department of Anesthesia, Sunnybrook Health Science Center, Toronto, Ontario, Canada

Submitted 27 April 2007; accepted in final form 17 August 2007

GABA_A receptors generate both phasic and tonic forms of inhibition. In hippocampal pyramidal neurons, GABA_A receptors that contain the 5 subunit generate a tonic inhibitory conductance. The physiological role of this tonic inhibition is uncertain, although 5GABA_A receptors are known to influence hippocampal-dependent learning and memory processes. Here we provide evidence that 5GABA_A receptors regulate the strength of the depolarizing stimulus that is required to generate an action potential in pyramidal neurons. Neurons from 5 knock-out (5–/–) and wild-type (WT) mice were studied in brain slices and cell cultures using whole cell and perforated-patch-clamp techniques. Membrane resistance was 1.6-fold greater in 5–/– than in WT neurons, but the resting membrane potential and chloride equilibrium potential were similar. Membrane hyperpolarization evoked by an application of exogenous GABA was greater in WT neurons. Inhibiting the function of 5GABA_A receptor with nonselective (picrotoxin) or 5 subunit-selective (L-655,708) compounds depolarized WT neurons by 3 mV, whereas no change was detected in 5–/– neurons. The depolarizing current required to generate an action potential was twofold greater in WT than in 5–/– neurons, whereas the slope of the input-output relationship for action potential firing was similar. We conclude that shunting inhibition mediated by 5GABA_A receptors regulates the firing of action potentials and may synchronize network activity that underlies hippocampal-dependent behavior.

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