Zou Wenjie, Guo Zhipeng, Suo Longge, Zhu Jianping, He Haiyang, Li Xiufeng, Wang Kewan, Chen Rongqing
Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Front Cell Dev Biol. 2022 Dec 15;10:1031872. doi: 10.3389/fcell.2022.1031872. eCollection 2022.
Temporal lobe epilepsy (TLE) is the most common form of epilepsy with focal seizures which in some conditions can develop into secondarily generalized tonic-clonic seizures by the propagation of epileptic activities in the temporal lobe to other brain areas. The nucleus accumbens (NAc) has been suggested as a treatment target for TLE as accumulating evidence indicates that the NAc, especially its shell, participates in the process of epileptic seizures of patients and animal models with TLE. The majority of neurons in the NAc are GABAergic medium spiny neurons (MSNs) expressing dopamine receptor D1 (D1R) or dopamine receptor D2 (D2R). However, the direct evidence of the NAc shell participating in the propagation of TLE seizures is missing, and its cell type-specific modulatory roles in TLE seizures are unknown. In this study, we microinjected kainic acid into basolateral amygdala (BLA) to make a mouse model of TLE with initial focal seizures and secondarily generalized seizures (SGSs). We found that TLE seizures caused robust c-fos expression in the NAc shell and increased neuronal excitability of D1R-expressing MSN (D1R-MSN) and D2R-expressing MSN (D2R-MSN). Pharmacological inhibition of the NAc shell alleviated TLE seizures by reducing the number of SGSs and seizure stages. Cell-type-specific chemogenetic inhibition of either D1R-MSN or D2R-MSN showed similar effects with pharmacological inhibition of the NAc shell. Both pharmacological and cell-type-specific chemogenetic inhibition of the NAc shell did not alter the onset time of focal seizures. Collectively, these findings indicate that the NAc shell and its D1R-MSN or D2R-MSN mainly participate in the propagation and generalization of the TLE seizures.
颞叶癫痫（TLE）是最常见的伴有局灶性发作的癫痫类型，在某些情况下，颞叶中的癫痫活动会传播至其他脑区，进而发展为继发性全身性强直阵挛发作。伏隔核（NAc）已被认为是TLE的一个治疗靶点，因为越来越多的证据表明，NAc，尤其是其壳核，参与了TLE患者和动物模型的癫痫发作过程。NAc中的大多数神经元是表达多巴胺受体D1（D1R）或多巴胺受体D2（D2R）的γ-氨基丁酸能中等棘状神经元（MSN）。然而，NAc壳核参与TLE发作传播的直接证据尚缺失，其在TLE发作中的细胞类型特异性调节作用也不清楚。在本研究中，我们向基底外侧杏仁核（BLA）微量注射 kainic 酸，制作了一个具有初始局灶性发作和继发性全身性发作（SGSs）的TLE小鼠模型。我们发现，TLE发作导致NAc壳核中c-fos表达增强，并增加了表达D1R的MSN（D1R-MSN）和表达D2R的MSN（D2R-MSN）的神经元兴奋性。对NAc壳核进行药理学抑制可通过减少SGSs的数量和发作阶段来减轻TLE发作。对D1R-MSN或D2R-MSN进行细胞类型特异性化学遗传学抑制显示出与对NAc壳核进行药理学抑制相似的效果。对NAc壳核进行药理学和细胞类型特异性化学遗传学抑制均未改变局灶性发作的起始时间。总体而言，这些发现表明，NAc壳核及其D1R-MSN或D2R-MSN主要参与TLE发作的传播和泛化。
