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The Journal of Neuroscience, July 11, 2007, 27(28):7520-7531; doi:10.1523/JNEUROSCI.1555-07.2007

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

Nianhui Zhang,¹ Weizheng Wei,² Istvan Mody,^2,3 and Carolyn R. Houser^1,3,4

¹Departments of Neurobiology and ²Neurology and Physiology, and ³Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, and ⁴Research Service, Veterans Administration Greater Los Angeles Healthcare System, West Los Angeles, Los Angeles, California 90073

Correspondence should be addressed to Dr. Carolyn R. Houser, Department of Neurobiology, CHS 73-235, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1763. Email: houser{at}mednet.ucla.edu

Complex changes in GABA_A receptors (GABA_ARs) in animal models of temporal lobe epilepsy during the chronic period include a decrease in the subunit and increases in the 4 and 2 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 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 GABA_ARs. An insensitivity of the tonic current to the neurosteroid tetrahydrodeoxy-corticosterone was consistent with decreased expression of the subunit. In the pilocarpine-treated mice, 4 subunit labeling remained at perisynaptic locations, but increased 2 subunit labeling was also found at many perisynaptic locations on granule cell dendrites, consistent with a shift of the 2 subunit from synaptic to perisynaptic locations and potential partnership of the 4 and 2 subunits in the epileptic animals. The decreased 2 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 GABA_AR 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.

Key words: immunogold labeling; electron microscopy; dentate gyrus; tonic inhibition; neurosteroids; pilocarpine; temporal lobe epilepsy

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Received April 6, 2007; revised May 29, 2007; accepted June 5, 2007.

Correspondence should be addressed to Dr. Carolyn R. Houser, Department of Neurobiology, CHS 73-235, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1763. Email: houser{at}mednet.ucla.edu

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