Verena C Wimmer1, Melody Y-S Li1, Samuel F Berkovic1, Steven Petrou2. 1. From The Florey Institute of Neuroscience and Mental Health (V.C.W., M.Y.-S.L., S.P.) and Centre for Neuroscience (S.P.), University of Melbourne; and Epilepsy Research Centre and Department of Medicine (S.F.B.), University of Melbourne, Austin Health, Australia. 2. From The Florey Institute of Neuroscience and Mental Health (V.C.W., M.Y.-S.L., S.P.) and Centre for Neuroscience (S.P.), University of Melbourne; and Epilepsy Research Centre and Department of Medicine (S.F.B.), University of Melbourne, Austin Health, Australia. spetrou@unimelb.edu.au.
Abstract
OBJECTIVE: The human GABAAγ2(R43Q) mutation is associated with genetic epilepsy. Because of the role of γ-aminobutyric acid (GABA) in brain development, we asked whether this epilepsy mutation might affect excitability by changing cortical cytoarchitecture. METHODS: We used a mouse model harboring a heterozygous R43Q missense mutation in the GABAA receptor subunit γ2, as identified in a family with absence epilepsy and febrile seizures. Three-dimensional quantification of immunostained neurons (NeuN), inhibitory neurons (GABA), and inhibitory neuron subpopulations (calretinin, parvalbumin, and calbindin) was performed in fiducial somatosensory cortical columns of seizure-naive GABAAγ2(R43Q) and control mice. RESULTS: Of note, the densities of GABA-, calretinin-, parvalbumin-, and calbindin-containing neurons were increased, and somewhat perplexing, the ratio between putative excitatory and inhibitory neurons was decreased in GABAAγ2(R43Q) mice. Differences were detected in a layer-specific manner with greater overall effects in layers 2/3, 5, and 6, as compared with layers 1 and 4. CONCLUSIONS: Our results suggest that the γ2(R43Q) mutation significantly affects cortical microcircuitry in the cortex of this model of human genetic epilepsy.
OBJECTIVE: The human GABAAγ2(R43Q) mutation is associated with genetic epilepsy. Because of the role of γ-aminobutyric acid (GABA) in brain development, we asked whether this epilepsy mutation might affect excitability by changing cortical cytoarchitecture. METHODS: We used a mouse model harboring a heterozygous R43Q missense mutation in the GABAA receptor subunit γ2, as identified in a family with absence epilepsy and febrile seizures. Three-dimensional quantification of immunostained neurons (NeuN), inhibitory neurons (GABA), and inhibitory neuron subpopulations (calretinin, parvalbumin, and calbindin) was performed in fiducial somatosensory cortical columns of seizure-naive GABAAγ2(R43Q) and control mice. RESULTS: Of note, the densities of GABA-, calretinin-, parvalbumin-, and calbindin-containing neurons were increased, and somewhat perplexing, the ratio between putative excitatory and inhibitory neurons was decreased in GABAAγ2(R43Q) mice. Differences were detected in a layer-specific manner with greater overall effects in layers 2/3, 5, and 6, as compared with layers 1 and 4. CONCLUSIONS: Our results suggest that the γ2(R43Q) mutation significantly affects cortical microcircuitry in the cortex of this model of humangenetic epilepsy.
Authors: Istvan Adorjan; Bashir Ahmed; Virginia Feher; Mario Torso; Kristine Krug; Margaret Esiri; Steven A Chance; Francis G Szele Journal: Brain Date: 2017-07-01 Impact factor: 13.501
Authors: Mangor Pedersen; Magdalena Kowalczyk; Amir Omidvarnia; Piero Perucca; Samuel Gooley; Steven Petrou; Ingrid E Scheffer; Samuel F Berkovic; Graeme D Jackson Journal: Neurol Genet Date: 2019-06-07