Aberrant GABA sub(A) Receptor Expression in the Dentate Gyrus of the Epileptic Mutant Mouse Stargazer

Stargazer (stg) mutant mice fail to express stargazin [transmembrane AMPA receptor regulatory protein gamma 2 (TARP gamma 2)] and consequently experience absence seizure-like thalamocortical spike-wave discharges that pervade the hippocampal formation via the dentate gyrus (DG). As in other seizure models, the dentate granule cells of stg develop elaborate reentrant axon collaterals and transiently overexpress brain-derived neurotrophic factor. We investigated whether GABAergic parameters were affected by the stg mutation in this brain region. GABA sub(A) receptor (GABAR) alpha 4 and beta 3 subunits were consistently upregulated, GABAR delta expression appeared to be variably reduced, whereas GABAR alpha 1, beta 2, and gamma 2 subunits and the GABAR synaptic anchoring protein gephyrin were essentially unaffected. We established that the alpha 4 beta gamma 2 subunit-containing, flunitrazepam-insensitive subtype of GABARs, not normally a significant GABAR in DG neurons, was strongly upregulated in stg DG, apparently arising at the expense of extrasynaptic alpha 4 beta delta -containing receptors. This change was associated with a reduction in neurosteroid-sensitive GABAR-mediated tonic current. This switch in GABAR subtypes was not reciprocated in the tottering mouse model of absence epilepsy implicating a unique, intrinsic adaptation of GABAergic networks in stg. Contrary to previous reports that suggested that TARP gamma 2 is expressed in the dentate, we find that TARP gamma 2 was neither detected in stg nor control DG. We report that TARP gamma 8 is the principal TARP isoform found in the DG and that its expression is compromised by the stargazer mutation. These effects on GABAergic parameters and TARP gamma 8 expression are likely to arise as a consequence of failed expression of TARP gamma 2 elsewhere in the brain, resulting in hyperexcitable inputs to the dentate.