Circuit-specific intracortical hyperconnectivity in mice with deletion of the autism-associated Met receptor tyrosine kinase.
Circuit-specific intracortical hyperconnectivity in mice with deletion of the autism-associated Met receptor tyrosine kinase.
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DOI：
10.1523/jneurosci.6569-10.2011
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发表时间：
2011-04-13
期刊：
影响因子：
--
通讯作者：
Shepherd GM
中科院分区：
文献类型：
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作者：
Qiu S;Anderson CT;Levitt P;Shepherd GM
新皮层局部超连接是自闭症谱系障碍（ASD）的一种假设病理生理状态。MET是一种调节树突和脊柱形态发生的受体酪氨酸激酶，已被确定为ASD的风险基因。在这里，我们分析了脑白质背侧来源的条件敲除（cKO）小鼠的前额叶皮层中已鉴定的锥体神经元的突触回路组织。通过谷氨酸释放的突触图谱发现，2/3层是对照组第5层投射神经元局部兴奋性输入的主要来源。在cKO和杂合子中，这一途径都要强2倍。这种增加是亚层和投影类特异性的，仅限于上层5B的皮质纹状体神经元，而不是邻近的皮质孔顶神经元。cKO切片的成对记录显示单一性连接增强。我们认为，特定新皮层微回路中的兴奋性超连通性构成了met介导的ASD风险的生理基础。
Local hyperconnectivity in the neocortex is a hypothesized pathophysiological state in autism spectrum disorder (ASD). MET, a receptor tyrosine kinase that regulates dendrite and spine morphogenesis, has been established as a risk gene for ASD. Here, we analyzed the synaptic circuit organization of identified pyramidal neurons in the anterior frontal cortex of mice with a dorsal pallium derived, conditional knockout (cKO) of Met. Synaptic mapping by glutamate uncaging identified layer 2/3 as the main source of local excitatory input to layer 5 projection neurons in controls. In both cKO and heterozygotes this pathway was stronger by a factor of ~2. This increase was both sub-layer and projection-class specific, restricted to corticostriatal neurons in upper layer 5B, and not neighboring corticopontine neurons. Paired recordings in cKO slices demonstrated increased unitary connectivity. We propose that excitatory hyperconnectivity in specific neocortical microcircuits constitutes a physiological basis for Met-mediated ASD risk.