Abnormal Development of the Earliest Cortical Circuits in a Mouse Model of Autism Spectrum Disorder.
Abnormal Development of the Earliest Cortical Circuits in a Mouse Model of Autism Spectrum Disorder.
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DOI：
10.1016/j.celrep.2017.01.006
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发表时间：
2017-01-31
期刊：
影响因子：
8.8
通讯作者：
Kanold PO
中科院分区：
文献类型：
--
作者：
Nagode DA;Meng X;Winkowski DE;Smith E;Khan-Tareen H;Kareddy V;Kao JPY;Kanold PO
自闭症谱系障碍(ASD)涉及语音和声音处理方面的缺陷。早期发育过程中大脑皮层回路的变化可能是造成这种缺陷的原因之一。亚板神经元(SPN)形成最早的皮质微回路，是丘脑和皮质内回路正常发育所必需的。产前丙戊酸(VPA)会增加ASD的风险，特别是当出现在SPN发生的关键时间窗口时。利用小鼠听皮层的光路图谱，我们发现VPA暴露于E12改变了SPN的兴奋性和抑制性连接功能。环路改变主要表现为出生后第一周连接概率或强度增加的“斑块”，在出生后10天后，打开耳朵后不久，表现为普遍的高连接性。这些结果表明，产前暴露于VPA会严重影响大脑皮层回路的发育轨迹，而感觉驱动的活动可能会加剧早期的微妙连接缺陷。我们的发现确定该亚板可能是ASD缺陷的共同病理生理底物。
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 possible common pathophysiological substrate of deficits in ASD.