Altered Localization of GABAA Receptor Subunits on Dentate Granule Cell Dendrites Influences Tonic and Phasic Inhibition in a Mouse Model of Epilepsy

摘要

Complex changes in GABAA receptors (GABAARs) in animal models of temporal lobe epilepsy during the chronic period include a decrease in the δ subunit and increases in the α4 and γ2 subunits in the dentate gyrus. We used postembedding immunogold labeling to determine whether the subcellular locations of these subunits were also altered in pilocarpine-treated epileptic mice, and related functional changes were identified electrophysiologically. The ultrastructural studies confirmed a decrease in δ subunit labeling at perisynaptic locations in the molecular layer of the dentate gyrus where these subunits are critical for tonic inhibition. Unexpectedly, tonic inhibition in dentate granule cells was maintained in the epileptic mice, suggesting compensation by other GABAARs. An insensitivity of the tonic current to the neurosteroid tetrahydrodeoxy-corticosterone was consistent with decreased expression of the δ subunit. In the pilocarpine-treated mice, α4 subunit labeling remained at perisynaptic locations, but increased γ2 subunit labeling was also found at many perisynaptic locations on granule cell dendrites, consistent with a shift of the γ2 subunit from synaptic to perisynaptic locations and potential partnership of the α4 and γ2 subunits in the epileptic animals. The decreased γ2 labeling near the center of synaptic contacts was paralleled by a corresponding decrease in the dendritic phasic inhibition of granule cells in the pilocarpine-treated mice. These GABAAR subunit changes appear to impair both tonic and phasic inhibition, particularly at granule cell dendrites, and could reduce the adaptive responses of the GABA system in temporal lobe epilepsy.