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Human Molecular Genetics Advance Access published online on March 3, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn064
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Absence seizures in C3H/HeJ and knockout mice caused by mutation of the AMPA receptor subunit Gria4

Barbara Beyer1,&, Charlotte Deleuze2,&, Verity A. Letts1, Connie L. Mahaffey1, Rebecca M. Boumil1, Timothy A. Lew2, John R. Huguenard2 and Wayne N. Frankel1,*

1 The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609 2 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305

* Corresponding author The Jackson Laboratory 600 Main St, Bar Harbor, ME phone 04609 207 288 6354 FAX 207 288 6757 email wayne.frankel{at}jax.org

Received December 4, 2007; Revised February 28, 2008; Accepted February 28, 2008

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 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 spkw1homozygotes. Gria3and Gria4encode 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.

& These authors contributed equally to this work.


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