Department of Anatomy, School of Biomedical Sciences, and the Brain Health Research Centre, University of Otago, P.O. Box 913, Dunedin 9054, New Zealand.
Int J Mol Sci. 2022 Dec 10;23(24):15685. doi: 10.3390/ijms232415685.
Absence seizures are hyperexcitations within the cortico-thalamocortical (CTC) network, however the underlying causative mechanisms at the cellular and molecular level are still being elucidated and appear to be multifactorial. Dysfunctional feed-forward inhibition (FFI) is implicated as one cause of absence seizures. Previously, we reported altered excitation onto parvalbumin-positive (PV) interneurons in the CTC network of the stargazer mouse model of absence epilepsy. In addition, downstream changes in GABAergic neurotransmission have also been identified in this model. Our current study assessed whether dysfunctional FFI affects GABA receptor (GABAR) subunit expression in the stargazer primary somatosensory cortex (SoCx). Global tissue expression of GABAR subunits α1, α3, α4, α5, β2, β3, γ2 and δ were assessed using Western blotting (WB), while biochemically isolated subcellular fractions were assessed for the α and δ subunits. We found significant reductions in tissue and synaptic expression of GABAR α1, 18% and 12.2%, respectively. However, immunogold-cytochemistry electron microscopy (ICC-EM), conducted to assess GABAR α1 specifically at synapses between PV interneurons and their targets, showed no significant difference. These data demonstrate a loss of phasic GABAR α1, indicating altered GABAergic inhibition which, coupled with dysfunctional FFI, could be one mechanism contributing to the generation or maintenance of absence seizures.
失神发作是皮质-丘脑-皮质（CTC）网络中的过度兴奋，然而，细胞和分子水平的潜在因果机制仍在阐明中，似乎是多因素的。功能失调的前馈抑制（FFI）被认为是失神发作的一个原因。以前，我们报道了在失神癫痫的星状细胞模型的 CTC 网络中，对 PV 阳性（PV）中间神经元的兴奋作用发生改变。此外，在该模型中还发现了 GABA 能神经传递的下游变化。我们目前的研究评估了功能失调的 FFI 是否会影响星状细胞原发性体感皮层（SoCx）中的 GABA 受体（GABAR）亚基表达。使用 Western blot（WB）评估 GABAR 亚基 α1、α3、α4、α5、β2、β3、γ2 和 δ 的组织和突触表达的整体水平，而通过生物化学分离的亚细胞级分评估 α 和 δ 亚基。我们发现组织和突触 GABARα1 的表达分别显著降低了 18%和 12.2%。然而，进行免疫金细胞化学电子显微镜（ICC-EM）以评估 PV 中间神经元与其靶标之间的突触处的 GABARα1 ，并未显示出显著差异。这些数据表明，相位 GABARα1 的丧失表明 GABA 能抑制作用发生改变，与功能失调的 FFI 相结合，可能是导致或维持失神发作的一种机制。
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