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

Abstract

Complex changes in GABA A receptors (GABA A Rs) 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 A Rs. 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 A R 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.

Long-term sensory deprivation selectively rearranges functional inhibitory circuits in mouse barrel cortex

“…Although we show an increase in ␣1 function, data from the present study indicate that possible changes may involve alterations that do not involve changes in expression levels, such as phosphorylation (39). A major redistribution of ␣1 subunits from synaptic to extrasynaptic locations on the cell membrane appears unlikely, because we observed no significant changes in rise times (40). Our finding of increased ␣1 subunit functionality does not rule out additional contributions to altered IPSC properties through presynaptic mechanisms, such as altered structure of presynaptic terminals or the selective loss of specific types of presynaptic inhibitory neurons (12,(40)(41)(42)(43)(44)(45).…”

Enhancement of GABA A -current run-down in the hippocampus occurs at the first spontaneous seizure in a model of temporal lobe epilepsy

“…However, this may be just one among other possible molecular mechanisms, because substantial alterations in several other subunits have been reported in association with epilepsy. For example, expression of the δ-subunit has been reported to be consistently reduced in granule cell dendrites (25, 33, 34) and may be substituted by γ2-subunits, resulting in impairment of both tonic and phasic GABA transmission (35). Furthermore, verification at single cell level will be essential to conclusively demonstrate that alterations in receptor composition are responsible for the increased run-down.…”

Decrease in Tonic Inhibition Contributes to Increase in Dentate Semilunar Granule Cell Excitability after Brain Injury

“…Consequently, post-traumatic decrease in tonic inhibition may compromise the ability of SGCs to participate in input discrimination and contribute to memory and cognitive disabilities following brain injury. Although decrease in tonic inhibition can lower seizure thresholds (Maguire et al, 2005), granule cell tonic GABA current is enhanced or unchanged in acquired epilepsy (Zhang et al, 2007;Zhan and Nadler, 2009;Mtchedlishvili et al, 2010). How enhanced tonic GABA currents influence seizure thresholds is unclear since, while increased GABA conductance may limit excitability, depolarizing shifts in GABA reversal (Bonislawski et al, 2007;Pathak et al, 2007) tend to augment excitability.…”

“…Tonic inhibition can contribute substantially to resting membrane conductance and regulate neuronal gain and excitability (Mitchell and Silver, 2003;Ruiz et al, 2003;Chadderton et al, 2004;Farrant and Nusser, 2005). Receptors underlying granule cell tonic GABA currents are known to be altered in models of acquired epilepsy (Peng et al, 2004;Zhang et al, 2007;Zhan and Nadler, 2009;Rajasekaran et al, 2010), including cortical impact injury (Mtchedlishvili et al, 2010). However, whether the source of inhibitory inputs to SGCs is the same as that of granule cells, whether SGCs have tonic GABA currents, and if brain injury modifies synaptic and tonic inhibition in SGCs, is not known.…”