Aberrant GABA_AReceptor 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 (TARP␥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 A 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 ␣4␤␥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 ␣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.Contrary to previous reports that suggested that TARP␥2 is expressed in the dentate, we find that TARP␥2 was neither detected in stg nor control DG. We report that TARP␥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␥8 expression are likely to arise as a consequence of failed expression of TARP␥2 elsewhere in the brain, resulting in hyperexcitable inputs to the dentate.

Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2

“…To date, CACNG2 has mostly been studied within the context of epilepsy (Moss et al 2003;Payne et al 2006;Ryu et al 2008). In this regard, the potential relationship between mechanisms of epilepsy and neuropathic pain is noteworthy (Devor 2006b).…”

Differential cerebellar GABAA receptor expression in mice with mutations in CaV2.1 (P/Q-type) calcium channels

“…Yet, there are no existing pharmaceutical intervention approaches that target GABAergic neurotransmission in ataxia despite strong evidence for its involvement in the pathophysiology of ataxia in rodents (Kaja et al, 2007a; Payne et al, 2006; Yamaguchi et al, 1984; present study) and patients (Kish et al, 1983; Perry et al, 1984). Notably, ataxia associated with benzodiazepine treatment is clinically well-established and has recently been linked to the GABA A R α 1 subunit in rodents, primates and humans (McKernan et al, 2000; Milic et al, 2012; Platt et al, 2002).…”

“…Overall B max and K D values were obtained by calculating the mean values obtained from each individual animal. Rosenthal transformations were performed on radioligand binding data and plotted as Scatchard plots for illustration purposes only (Kaja et al, 2007a; Payne et al, 2006; Thompson et al, 1998). …”

GABAA Receptor Expression in the Forebrain of Ataxic Rolling Nagoya Mice

“…Overall B max and K D values were obtained by calculating the mean values obtained from each individual animal. Rosenthal transformations were performed on radioligand binding data and plotted as Scatchard plots for illustration purposes only [23,25,26]. Statistically significant differences were tested for using Student’s t -tests, as appropriate.…”