Department of Psychiatry, Neuroscience Program and the Nina Ireland Laboratory of Developmental Neurobiology, University of California San Francisco, San Francisco, CA, USA.
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
Cereb Cortex. 2018 Nov 1;28(11):3797-3815. doi: 10.1093/cercor/bhx241.
The postnatal functions of the Dlx1&2 transcription factors in cortical interneurons (CINs) are unknown. Here, using conditional Dlx1, Dlx2, and Dlx1&2 knockouts (CKOs), we defined their roles in specific CINs. The CKOs had dendritic, synaptic, and survival defects, affecting even PV+ CINs. We provide evidence that DLX2 directly drives Gad1, Gad2, and Vgat expression, and show that mutants had reduced mIPSC amplitude. In addition, the mutants formed fewer GABAergic synapses on excitatory neurons and had reduced mIPSC frequency. Furthermore, Dlx1/2 CKO had hypoplastic dendrites, fewer excitatory synapses, and reduced excitatory input. We provide evidence that some of these phenotypes were due to reduced expression of GRIN2B (a subunit of the NMDA receptor), a high confidence Autism gene. Thus, Dlx1&2 coordinate key components of CIN postnatal development by promoting their excitability, inhibitory output, and survival.
Dlx1 和 Dlx2 转录因子在皮质中间神经元 (CINs) 中的产后功能尚不清楚。在这里，我们使用条件性 Dlx1、Dlx2 和 Dlx1&2 敲除 (CKO)，定义了它们在特定 CINs 中的作用。CKO 存在树突、突触和存活缺陷，甚至影响到 PV+ CINs。我们提供的证据表明，DLX2 直接驱动 Gad1、Gad2 和 Vgat 的表达，并表明突变体的 mIPSC 幅度减小。此外，突变体在兴奋性神经元上形成的 GABA 能突触较少，mIPSC 频率降低。此外，Dlx1/2 CKO 具有发育不良的树突、较少的兴奋性突触和减少的兴奋性输入。我们提供的证据表明，这些表型中的一些是由于 NMDA 受体 (NR) 的亚基 GRIN2B 的表达减少引起的，GRIN2B 是一种高度可信的自闭症基因。因此，Dlx1&2 通过促进 CIN 产后发育的兴奋性、抑制性输出和存活来协调关键成分。
