title: Spike-and-wave discharge mediated reduction in hippocampal HCN1 channel function associates with learning deficits in a genetic mouse model of epilepsy.
abstract: The GABAAγ2(R43Q) mouse is an established model of absence epilepsy displaying spontaneous spike-and-wave discharges (SWD) and associated behavioral arrest. Absence epilepsy typically results from cortico-thalamic networks. Nevertheless, there is increasing evidence for changes in hippocampal metabolism and electrical behavior, consistent with a link between absence seizures and hippocampus-related co-morbidities. Hyperpolarization-activated-cyclic-nucleotide-gated (HCN) channels are known to be transcriptionally regulated in a number of seizure models. Here we investigate the expression and function of these channels in the hippocampus of the genetic epilepsy model. A reduction in HCN1, but not HCN2 transcript, was observed in GABAAγ2(R43Q) mice relative to their littermate controls. In contrast, no change in HCN1 transcript was noted at an age prior to seizure expression or in a SWD-free model in which the R43Q mutation has been crossed into a seizure-resistant genetic background. Whole-cell recordings from CA1 pyramidal neurons confirm a reduction in Ih in the GABAAγ2(R43Q) mouse. Further, a left-shift in half-activation of the Ih conductance-voltage relationship is consistent with a reduction in HCN1 with no change in HCN2 channel expression. Behavioral analysis using the Morris water maze indicates that GABAAγ2(R43Q) mice are unable to learn as effectively as their wildtype littermates suggesting a deficit in hippocampal-based learning. SWD-free mice harboring the R43Q mutation had no learning deficit. We conclude that SWDs reduce hippocampal HCN1 expression and function, and that the reduction associates with a spatial learning deficit.
authors.affiliation: Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville 3010, Australia; Department of Genetics, University of Melbourne, Parkville 3010, Australia. Electronic address: m.phillips@unimelb.edu.au.
authors.forename: A Marie
authors.initials: AM
authors.lastname: Phillips
authors.affiliation: Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville 3010, Australia; Centre for Neural Engineering, The University of Melbourne, Parkville 3010, Melbourne, Australia. Electronic address: kaarkim@gmail.com.
authors.forename: Taehwan
authors.initials: T
authors.lastname: Kim
authors.affiliation: Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville 3010, Australia. Electronic address: e.vargas@commercial.unimelb.edu.au.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Vargas
authors.affiliation: Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville 3010, Australia; Centre for Neural Engineering, The University of Melbourne, Parkville 3010, Melbourne, Australia; Department of Anatomy and Neuroscience, The University of Melbourne, Parkville 3010, Melbourne, Australia. Electronic address: steven.petrou@florey.edu.au.
authors.forename: Steven
authors.initials: S
authors.lastname: Petrou
authors.affiliation: Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville 3010, Australia. Electronic address: careid@unimelb.edu.au.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Reid
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000503:physiopathology; D015897:Comorbidity; D004832:Epilepsy, Absence / Q000453:epidemiology / Q000503:physiopathology*; D005260:Female; D006624:Hippocampus / Q000503:physiopathology*; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000378:metabolism*; D007859:Learning Disabilities / Q000453:epidemiology / Q000503:physiopathology*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009154:Mutation; D015221:Potassium Channels / Q000378:metabolism*; D017966:Pyramidal Cells / Q000503:physiopathology; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism; D012640:Seizures / Q000209:etiology / Q000503:physiopathology
chemical_list: C546279:GABRG2 protein, human; C578666:Hcn1 protein, mouse; C578711:Hcn2 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015221:Potassium Channels; D011963:Receptors, GABA-A
keywords: Absence epilepsy; CA1 pyramidal; Co-morbidity; HCN1; I(h); Memory