title: Migraine mutations impair hippocampal learning despite enhanced long-term potentiation.
abstract: To explain cognitive and memory difficulties observed in some familial hemiplegic migraine (FHM) patients, we examined hippocampal neurotransmission and plasticity in knock-in mice expressing the FHM type 1 (FHM1) R192Q gain-of function mutation in the CACNA1A gene that encodes the α1A subunit of neuronal CaV2.1 channels. We determined stimulus intensity-response curves for anterior commissure-evoked hippocampal CA1 field potentials in strata pyramidale and radiatum and assessed neuroplasticity by inducing long-term potentiation (LTP) and long-term depression (LTD) in anesthetized mice in vivo. We also studied learning and memory using contextual fear-conditioning, Morris water maze, and novel object recognition tests. Hippocampal field potentials were significantly enhanced in R192Q mice compared with wild-type controls. Stimulus intensity-response curves were shifted to the left and displayed larger maxima in the mutants. LTP was augmented by twofold in R192Q mice, whereas LTD was unchanged compared with wild-type mice. R192Q mice showed significant spatial memory deficits in contextual fear-conditioning and Morris water maze tests compared with wild-type controls. Novel object recognition was not impaired in R192Q mice; however, mice carrying the more severe S218L CACNA1A mutation showed marked deficits in this test, suggesting a genotype-phenotype relationship. Thus, whereas FHM1 gain-of-function mutations enhance hippocampal excitatory transmission and LTP, learning and memory are paradoxically impaired, providing a possible explanation for cognitive changes detected in FHM. Data suggest that abnormally enhanced plasticity can be as detrimental to efficient learning as reduced plasticity and highlight how genetically enhanced neuronal excitability may impact cognitive function.
authors.affiliation: Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129.
authors.forename: Ergin
authors.initials: E
authors.lastname: Dilekoz
authors.affiliation: Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, Departments of Neurology and.
authors.forename: Thijs
authors.initials: T
authors.lastname: Houben
authors.affiliation: Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129.
authors.forename: Katharina
authors.initials: K
authors.lastname: Eikermann-Haerter
authors.affiliation: Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Balkaya
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, 1081 HV Amsterdam, The Netherlands.
authors.forename: A Mariette
authors.initials: AM
authors.lastname: Lenselink
authors.affiliation: Department of Pediatric Critical Care Medicine and.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Whalen
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, 1081 HV Amsterdam, The Netherlands.
authors.forename: Sabine
authors.initials: S
authors.lastname: Spijker
authors.affiliation: Departments of Neurology and.
authors.forename: Michel D
authors.initials: MD
authors.lastname: Ferrari
authors.affiliation: Departments of Neurology and Human Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
authors.affiliation: Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 cayata@partners.org.
authors.forename: Cenk
authors.initials: C
authors.lastname: Ayata
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000502:physiology* / Q000503:physiopathology; D020864:Calcium Channels, N-Type / Q000235:genetics*; D003214:Conditioning, Classical; D005239:Fear; D005260:Female; D017774:Long-Term Potentiation; D036881:Long-Term Synaptic Depression; D008297:Male; D018782:Maze Learning; D051379:Mice; D020325:Migraine with Aura / Q000235:genetics* / Q000503:physiopathology; D020125:Mutation, Missense
chemical_list: D020864:Calcium Channels, N-Type
keywords: hippocampus; learning; long-term depression; long-term potentiation; memory; migraine