title: Hyperpolarization-activated current (In) is reduced in hippocampal neurons from Gabra5-/- mice.
abstract: Changes in the expression of γ-aminobutyric acid type A (GABAA) receptors can either drive or mediate homeostatic alterations in neuronal excitability. A homeostatic relationship between α5 subunit-containing GABAA (α5GABAA) receptors that generate a tonic inhibitory conductance, and HCN channels that generate a hyperpolarization-activated cation current (Ih) was recently described for cortical neurons, where a reduction in Ih was accompanied by a reciprocal increase in the expression of α5GABAA receptors resulting in the preservation of dendritosomatic synaptic function. Here, we report that in mice that lack the α5 subunit gene (Gabra5-/-), cultured embryonic hippocampal pyramidal neurons and ex vivo CA1 hippocampal neurons unexpectedly exhibited a decrease in Ih current density (by 40% and 28%, respectively), compared with neurons from wild-type (WT) mice. The resting membrane potential and membrane hyperpolarization induced by blockade of Ih with ZD-7288 were similar in cultured WT and Gabra5-/- neurons. In contrast, membrane hyperpolarization measured after a train of action potentials was lower in Gabra5-/- neurons than in WT neurons. Also, membrane impedance measured in response to low frequency stimulation was greater in cultured Gabra5-/- neurons. Finally, the expression of HCN1 protein that generates Ih was reduced by 41% in the hippocampus of Gabra5-/- mice. These data indicate that loss of a tonic GABAergic inhibitory conductance was followed by a compensatory reduction in Ih. The results further suggest that the maintenance of resting membrane potential is preferentially maintained in mature and immature hippocampal neurons through the homeostatic co-regulation of structurally and biophysically distinct cation and anion channels.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Bonin
authors.forename: Agnieszka A
authors.initials: AA
authors.lastname: Zurek
authors.forename: Jieying
authors.initials: J
authors.lastname: Yu
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Bayliss
authors.forename: Beverley A
authors.initials: BA
authors.lastname: Orser
mesh_terms: D000818:Animals; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000378:metabolism; D017097:Electric Impedance; D055724:Electrophysiological Phenomena; D006624:Hippocampus / Q000166:cytology*; D006706:Homeostasis; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D008564:Membrane Potentials; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism; D011963:Receptors, GABA-A / Q000172:deficiency*; D015854:Up-Regulation
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; C496250:Gabra5 protein, mouse; C578666:Hcn1 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015221:Potassium Channels; D011963:Receptors, GABA-A