Absence seizures in C3H/HeJ and knockout mice caused by mutation of the AMPA receptor subunit Gria4
Autor: | John R. Huguenard, Charlotte Deleuze, Rebecca M. Boumil, Verity A. Letts, Connie L. Mahaffey, Barbara Beyer, Timothy A Lew, Wayne N. Frankel |
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Rok vydání: | 2008 |
Předmět: |
medicine.medical_specialty
Molecular Sequence Data Thalamus AMPA receptor Biology Inhibitory postsynaptic potential Mice 03 medical and health sciences Epilepsy 0302 clinical medicine Internal medicine Convulsion Genetics medicine Animals Receptors AMPA Molecular Biology Genetics (clinical) 030304 developmental biology Mice Knockout Mice Inbred C3H 0303 health sciences Electroencephalography Articles General Medicine medicine.disease Null allele Cell biology Endocrinology medicine.anatomical_structure Epilepsy Absence Cerebral cortex Synapses Knockout mouse medicine.symptom 030217 neurology & neurosurgery |
Zdroj: | Human Molecular Genetics |
ISSN: | 1460-2083 0964-6906 |
Popis: | Absence epilepsy, characterized by spike–wave discharges (SWD) in the electroencephalogram, arises from aberrations within the circuitry of the cerebral cortex and thalamus that regulates awareness. The inbred mouse strain C3H/HeJ is prone to absence seizures, with a major susceptibility locus, spkw1, accounting for most of the phenotype. Here we find that spkw1 is associated with a hypomorphic retroviral-like insertion mutation in the Gria4 gene, encoding one of the four amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) receptor subunits in the brain. Consistent with this, Gria4 knockout mice also have frequent SWD and do not complement spkw1. In contrast, null mutants for the related gene Gria3 do not have SWD, and Gria3 loss actually lowers SWD of spkw1 homozygotes. Gria3 and Gria4 encode the predominant AMPA receptor subunits in the reticular thalamus, which is thought to play a central role in seizure genesis by inhibiting thalamic relay cells and promoting rebound burst firing responses. In Gria4 mutants, synaptic excitation of inhibitory reticular thalamic neurons is enhanced, with increased duration of synaptic responses—consistent with what might be expected from reduction of the kinetically faster subunit of AMPA receptors encoded by Gria4. These results demonstrate for the first time an essential role for Gria4 in the brain, and suggest that abnormal AMPA receptor-dependent synaptic activity can be involved in the network hypersynchrony that underlies absence seizures. |
Databáze: | OpenAIRE |
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