Abstracts

Increased excitatory drive in the thalamocortical network is thought to underlie absence seizures. Mutations in channels that mediate neuronal inhibition have been found in patients with familial forms of the disorder. However, the mutation in the Stargazer mouse, an animal model for absence epilepsy, primarily affects excitatory glutamatergic transmission via AMPA receptors. To date, stargazin and its related family members, the Transmembrane AMPA receptor Regulatory Proteins (TARPs), have only been shown to regulate synaptic AMPA receptor function in excitatory neurons. However, if TARPs also regulate AMPA receptors in inhibitory GABAergic neurons, the lack of inhibition may lead to seizure activity. Therefore the aim of this study was to determine if TARPs regulate AMPA receptors in GABAergic neurons., Single and double knockout mice for TARP isoforms [gamma]2 (stargazin) and [gamma]3 were generated. Western blotting was used to analyze AMPA receptor content in different brain regions. Synaptic AMPA receptor currents were measured with standard electrophysiological techniques in acute brain slices and dissociated neurons., Single [gamma]3-/- knockout mouse were indistinguishable from littermates. However, [gamma]2-/- [gamma]3-/- double knockout mice were severely impaired and generally died before the 2nd postnatal week. Western Blot analysis of [gamma]2-/- [gamma]3-/- double knockout mice found no change of AMPA receptor expression in most brain regions. Electrophysiological analysis of the GABAergic Purkinje neurons found a severe reduction of AMPA receptor mediated synaptic transmission in [gamma]2-/- mice, which was not increased in [gamma]2-/- [gamma]3-/- double knockout mice. A specific GABAergic interneuron population was found to be unaffected in single [gamma]2-/- and [gamma]3-/- knockout mice, but showed a nearly complete loss of synaptic AMPA receptors in [gamma]2-/- [gamma]3-/- double knockout mice., TARPs regulate AMPA receptors in GABAergic neurons, in addition to excitatory neurons. They can serve redundant roles as evidenced by the increasingly severe phenotype of double knockout mice., (Supported by Epilepsy Foundation; L[apos]Oreal USA for Women in Science Program; NIMH.)