Focal cortical dysplasia (FCD) is a major cause for drug-resistant epilepsies. The molecular and cellular mechanisms of epileptogenesis in FCD are still poorly understood. Some studies have suggested that deficiencies of γ-aminobutyric acid (GABA) system may play an important role in type II FCD, but it remains controversial. In order to examine whether and how GABAergic interneurons and synaptic function are affected, we generated a somatic mTOR hyperactivation-based mouse model of type II FCD by in utero electroporation, quantified densities of interneurons in the malformed cortices, and recorded miniature inhibitory postsynaptic currents in dysmorphic neurons. We detected 20–25% reduction of GABAergic interneurons within malformed cortices, independent of cortical regions and cell subtypes but proportionate to the decrease of global neuron counts. GABAergic synaptic transmission from interneurons to mTOR hyperactivated dysmorphic neurons was dramatically disrupted, outweighing the decrease of interneuron counts. Postnatal mTOR inhibition partially rescued these alterations of GABAergic system. We also quantified the expression of GABA_A receptor, GABA transporter, and chloridion transporter encoding genes and found that their expression was relatively intact within the malformed cortices. Taken together, these results confirmed that GABAergic interneuron and synapse transmission are disturbed profoundly in an mTOR-dependent manner in type II FCD. Our study suggests that postsynaptic mechanisms independent of interneuron reduction or altered expression of GABA synapse genes might be accountable for the impaired GABAergic neurotransmission in type II FCD as well as other mTOR-related epilepsies.

局灶性皮质发育不良（FCD）是耐药性癫痫的主要原因。FCD 癫痫发生的分子和细胞机制仍然知之甚少。一些研究表明γ-氨基丁酸（GABA）系统的缺陷可能在II型FCD中起重要作用，但仍存在争议。为了检查 GABA 能中间神经元和突触功能是否以及如何受到影响，我们通过宫内电穿孔生成了一个基于体细胞 mTOR 过度激活的 II 型 FCD 小鼠模型，量化畸形皮质中的中间神经元密度，并记录了微型抑制性突触后电流畸形神经元。我们检测到畸形皮质内 GABA 能中间神经元减少 20-25%，独立于皮质区域和细胞亚型，但与全局神经元计数的减少成正比。从中间神经元到 mTOR 过度激活的畸形神经元的 GABA 能突触传递被显着破坏，超过中间神经元数量的减少。出生后 mTOR 抑制部分挽救了 GABA 能系统的这些改变。我们还量化了 GABA 的表达_甲受体，GABA转运蛋白，和氯离子转运编码基因，并发现它们的表达是畸形的皮质内相对不变。总之，这些结果证实了在 II 型 FCD 中 GABA 能中间神经元和突触传递以 mTOR 依赖性方式受到严重干扰。我们的研究表明，独立于中间神经元减少或 GABA 突触基因表达改变的突触后机制可能是 II 型 FCD 以及其他 mTOR 相关癫痫中 GABA 能神经传递受损的原因。