Reduced hippocampal inhibition and enhanced autism-epilepsy comorbidity in mice lacking neuropilin 2.
Reduced hippocampal inhibition and enhanced autism-epilepsy comorbidity in mice lacking neuropilin 2.
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在缺乏神经菌素2的小鼠中，减少了海马区的抑制并增强了自闭症-癫痫共病。
DOI：
10.1038/s41398-021-01655-6
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发表时间：
2021-10-18
影响因子：
6.8
通讯作者：
Tran TS
中科院分区：
文献类型：
--
作者：
Eisenberg C;Subramanian D;Afrasiabi M;Ziobro P;DeLucia J;Hirschberg PR;Shiflett MW;Santhakumar V;Tran TS
神经纤毛蛋白受体及其分泌的脑信号蛋白配体通过调节许多关键的神经元过程（包括突触的成熟和GABA能中间神经元的迁移）在脑回路发育中发挥关键作用。与其发育作用一致，神经纤毛蛋白2（Nrp 2）基因座在自闭症谱系障碍（ASD）患者中含有多态性。nrp 2缺陷小鼠表现出自闭症样行为缺陷和癫痫发作倾向。为了确定Nrp 2缺乏的病理生理学，我们研究了海马的中间神经元亚型和海马CA 1区锥体神经元的抑制调节缺乏一个或两个副本的Nrp 2的小鼠的海马数。对中间神经元亚型的免疫染色显示，Nrp 2 −/−小鼠的小清蛋白、生长抑素和神经肽Y细胞数量减少，主要在CA 1中。全细胞记录发现，与年龄匹配的野生型对照组相比，Nrp 2 +/−和Nrp 2 −/−小鼠的CA 1锥体神经元静息膜电位的放电减少和超极化转变，表明内在兴奋性降低。同时，自发抑制性突触后电流（sIPSC）的频率和幅度在Nrp 2缺陷小鼠中降低。与Nrp 2 +/+动物相比，Nrp 2 −/−动物的惊厥剂量的红藻氨酸诱发的电图和行为癫痫发作的潜伏期显著更短，持续时间更长，严重程度更高。最后，Nrp 2 +/−和Nrp 2 −/−但不是Nrp 2 +/+小鼠的认知灵活性受损，这一点通过基于奖励的逆转学习（一种与海马电路功能相关的任务）得到了证明。总之，这些数据表明，Nrp 2 −/−小鼠的中间神经元亚型广泛减少，CA 1抑制受损，这可能导致癫痫发作易感性增加，行为缺陷与ASD/癫痫表型一致。
The neuropilin receptors and their secreted semaphorin ligands play key roles in brain circuit development by regulating numerous crucial neuronal processes, including the maturation of synapses and migration of GABAergic interneurons. Consistent with its developmental roles, the neuropilin 2 (Nrp2) locus contains polymorphisms in patients with autism spectrum disorder (ASD). Nrp2-deficient mice show autism-like behavioral deficits and propensity to develop seizures. In order to determine the pathophysiology in Nrp2 deficiency, we examined the hippocampal numbers of interneuron subtypes and inhibitory regulation of hippocampal CA1 pyramidal neurons in mice lacking one or both copies of Nrp2. Immunostaining for interneuron subtypes revealed that Nrp2−/− mice have a reduced number of parvalbumin, somatostatin, and neuropeptide Y cells, mainly in CA1. Whole-cell recordings identified reduced firing and hyperpolarized shift in resting membrane potential in CA1 pyramidal neurons from Nrp2+/− and Nrp2−/− mice compared to age-matched wild-type controls indicating decrease in intrinsic excitability. Simultaneously, the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) are reduced in Nrp2-deficient mice. A convulsive dose of kainic acid evoked electrographic and behavioral seizures with significantly shorter latency, longer duration, and higher severity in Nrp2−/− compared to Nrp2+/+ animals. Finally, Nrp2+/− and Nrp2−/− but not Nrp2+/+, mice have impaired cognitive flexibility demonstrated by reward-based reversal learning, a task associated with hippocampal circuit function. Together these data demonstrate a broad reduction in interneuron subtypes and compromised inhibition in CA1 of Nrp2−/− mice, which could contribute to the heightened seizure susceptibility and behavioral deficits consistent with an ASD/epilepsy phenotype.
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影响因子：
2
作者：
Havekes, Robbert;Nijholt, Ingrid M.;Van der Zee, Eddy A.
通讯作者：
Van der Zee, Eddy A.
影响因子：
1.9
作者：
Jeste SS;Tuchman R
通讯作者：
Tuchman R
影响因子：
3.1
作者：
Gupta A;Proddutur A;Chang YJ;Raturi V;Guevarra J;Shah Y;Elgammal FS;Santhakumar V
通讯作者：
Santhakumar V
影响因子：
3
作者：
Chaby, Lauren E.;Karavidha, Klevis;Liberzon, Israel
通讯作者：
Liberzon, Israel
影响因子：
6.8
作者：
D'Cruz AM;Mosconi MW;Ragozzino ME;Cook EH;Sweeney JA
通讯作者：
Sweeney JA