Aberrant GABA(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 gamma2 (TARPgamma2)] 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) alpha4 and beta3 subunits were consistently upregulated, GABAR delta expression appeared to be variably reduced, whereas GABAR alpha1, beta2, and gamma2 subunits and the GABAR synaptic anchoring protein gephyrin were essentially unaffected. We established that the alpha4 betagamma2 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 alpha4 betadelta-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 TARPgamma2 is expressed in the dentate, we find that TARPgamma2 was neither detected in stg nor control DG. We report that TARPgamma8 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 TARPgamma8 expression are likely to arise as a consequence of failed expression of TARPgamma2 elsewhere in the brain, resulting in hyperexcitable inputs to the dentate.
Payne
Helen L
HL
School of Biological and Biomedical Sciences, Science Research Laboratories, Durham University, Durham DH1 3LE, United Kingdom.
Donoghue
Peter S
PS
Connelly
William M K
WM
Hinterreiter
Sabine
S
Tiwari
Priyanka
P
Ives
Jane H
JH
Hann
Victoria
V
Sieghart
Werner
W
Lees
George
G
Thompson
Christopher L
CL
D000818:Animals; D015220:Calcium Channels / Q000172:deficiency; D002478:Cells, Cultured; D018891:Dentate Gyrus / Q000378:metabolism* / Q000503:physiopathology; D004594:Electrophysiology; D004832:Epilepsy, Absence / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008818:Mice, Neurologic Mutants / Q000378:metabolism*; D009473:Neuronal Plasticity; D020033:Protein Isoforms / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism; D014018:Tissue Distribution; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
C113940:Cacng2 protein, mouse; D015220:Calcium Channels; D020033:Protein Isoforms; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid