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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.

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