Aberrant GABA-A receptor expression in the dentate gyrus of the epileptic mutant mouse stargazer

Abstract

Stargazer (stg) mutant mice fail to express stargazin [transmembrane AMPA receptor regulatory protein 2 (TARP2)] 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. GABAA receptor (GABAR) 4 and 3 subunits were consistently upregulated, GABAR expression appeared to be variably reduced, whereas GABAR 1, 2, and 2 subunits and the GABAR synaptic anchoring protein gephyrin were essentially unaffected. We established that the 42 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 4-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.