Mutations in SYNGAP1, a protein enriched at glutamatergic synapses, cause intellectual disability associated with epilepsy, autism spectrum disorder, and sensory dysfunctions. Several studies showed that Syngap1 regulates the time course of forebrain glutamatergic synapse maturation; however, the developmental role of Syngap1 in inhibitory GABAergic neurons is less clear. GABAergic neurons can be classified into different subtypes based on their morphology, connectivity, and physiological properties. Whether Syngap1 expression specifically in parvalbumin (PV)-expressing and somatostatin (SST)-expressing interneurons, which are derived from the medial ganglionic eminence (MGE), plays a role in the emergence of distinct brain functions remains largely unknown. We used genetic strategies to generate Syngap1 haploinsufficiency in (1) prenatal interneurons derived from the medial ganglionic eminence, (2) in postnatal PV cells, and (3) in prenatal SST interneurons. We further performed in vivo recordings and behavioral assays to test whether and how these different genetic manipulations alter brain function and behavior in mice of either sex. Mice with prenatal-onset Syngap1 haploinsufficiency restricted to Nkx2.1-expressing neurons show abnormal cortical oscillations and increased entrainment induced by 40 Hz auditory stimulation but lack stimulus-specific adaptation. This latter phenotype was reproduced in mice with Syngap1 haploinsufficiency restricted to PV, but not SST, interneurons. Prenatal-onset Syngap1 haploinsufficiency in Nkx2.1-expressing neurons led to impaired social behavior and inability to extinguish fear memories; however, neither postnatal PV- nor prenatal SST-specific mutant mice show these phenotypes. We speculate that Syngap1 haploinsufficiency in prenatal/perinatal PV interneurons may contribute to cortical activity and cognitive alterations associated with Syngap1 mutations.

SYNGAP1是一种富含谷氨酸能突触的蛋白质，其突变会导致与癫痫、自闭症谱系障碍和感觉功能障碍相关的智力障碍。几项研究表明，Syngap1 调节前脑谷氨酸能突触成熟的时间进程;然而，Syngap1 在抑制性 GABA 能神经元中的发育作用尚不清楚。GABA 能神经元可根据其形态、连接性和生理特性分为不同的亚型。Syngap1 是否特异性表达于表达小白蛋白 （PV） 和生长抑素 （SST） 的中间神经元（来源于内侧神经节隆起 （MGE））在独特脑功能的出现中发挥作用在很大程度上仍然未知。我们使用遗传策略在 （1） 源自内侧神经节隆起的产前中间神经元、（2） 产后 PV 细胞和 （3） 产前 SST 中间神经元中产生 Syngap1 单倍体不足。我们进一步进行了体内记录和行为测定，以测试这些不同的基因操作是否以及如何改变任何性别小鼠的大脑功能和行为。产前发作的 Syngap1 单倍体功能不全仅限于表达 Nkx2.1 的神经元的小鼠表现出异常的皮层振荡和 40 Hz 听觉刺激诱导的夹带增加，但缺乏刺激特异性适应。后一种表型在 Syngap1 单倍体不足仅限于 PV 而不是 SST 中间神经元的小鼠中复制。表达 Nkx2.1 的神经元中产前发病的 Syngap1 单倍体不足导致社交行为受损，无法消除恐惧记忆;然而，出生后 PV 和产前 SST 特异性突变小鼠均未显示这些表型。 我们推测，产前/围产期 PV 中间神经元中的 Syngap1 单倍体不足可能导致与 Syngap1 突变相关的皮层活动和认知改变。