Nagode Daniel A, Meng Xiangying, Winkowski Daniel E, Smith Ed, Khan-Tareen Hamza, Kareddy Vishnupriya, Kao Joseph P Y, Kanold Patrick O
Department of Biology, University of Maryland, College Park, MD 20742, USA.
Center for Biomedical Engineering and Technology, and Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Cell Rep. 2017 Jan 31;18(5):1100-1108. doi: 10.1016/j.celrep.2017.01.006.
Autism spectrum disorder (ASD) involves deficits in speech and sound processing. Cortical circuit changes during early development likely contribute to such deficits. Subplate neurons (SPNs) form the earliest cortical microcircuits and are required for normal development of thalamocortical and intracortical circuits. Prenatal valproic acid (VPA) increases ASD risk, especially when present during a critical time window coinciding with SPN genesis. Using optical circuit mapping in mouse auditory cortex, we find that VPA exposure on E12 altered the functional excitatory and inhibitory connectivity of SPNs. Circuit changes manifested as "patches" of mostly increased connection probability or strength in the first postnatal week and as general hyper-connectivity after P10, shortly after ear opening. These results suggest that prenatal VPA exposure severely affects the developmental trajectory of cortical circuits and that sensory-driven activity may exacerbate earlier, subtle connectivity deficits. Our findings identify the subplate as a possible common pathophysiological substrate of deficits in ASD.
自闭症谱系障碍（ASD）涉及言语和声音处理方面的缺陷。早期发育过程中的皮质回路变化可能导致了这些缺陷。板下神经元（SPNs）形成最早的皮质微回路，是丘脑皮质和皮质内回路正常发育所必需的。产前接触丙戊酸（VPA）会增加患ASD的风险，尤其是在与SPN发生相吻合的关键时间窗口内接触时。利用小鼠听觉皮质中的光学回路映射技术，我们发现E12时接触VPA会改变SPNs的功能性兴奋性和抑制性连接。回路变化在出生后第一周表现为连接概率或强度大多增加的“斑块”，在P10（即耳张开后不久）后表现为普遍的高连接性。这些结果表明，产前接触VPA会严重影响皮质回路的发育轨迹，并且感觉驱动的活动可能会加剧早期细微的连接缺陷。我们的研究结果确定板下区域是ASD缺陷可能的共同病理生理底物。
