Neuroanatomical Alterations in the CNTNAP2 Mouse Model of Autism Spectrum Disorder.
Neuroanatomical Alterations in the CNTNAP2 Mouse Model of Autism Spectrum Disorder.
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DOI：
10.3390/brainsci13060891
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发表时间：
2023-05-31
期刊：
影响因子：
3.3
通讯作者：
Lee, Charles C.
中科院分区：
文献类型：
--
作者：
Gandhi, Tanya;Canepa, Cade R.;Adeyelu, Tolulope T.;Adeniyi, Philip A.;Lee, Charles C.
自闭症谱系障碍（ASD）与神经发育改变有关，包括非典型前脑细胞组织。几个ASD相关基因的突变通常导致大脑皮质异常，例如兴奋性锥体细胞的异常发育迁移和抑制性神经元回路的畸形。值得注意的是，CNTNAP 2基因的突变导致异位表层皮质神经元停滞在较低的皮质层，并改变皮质兴奋和抑制的平衡。然而，这些发现的更广泛的电路层面的影响以前没有被调查。因此，我们评估了CNTNAP 2突变小鼠的异位皮质神经元是否与高级丘脑核团形成异常连接，可能导致一些自闭症行为，如重复和多动行为。此外，我们评估了小白蛋白阳性（PV）皮质中间神经元及其专门的基质支持结构（称为神经元束膜网（PNNs））的发育是否在这些突变小鼠中发生了改变。我们发现，在CNTNAP 2突变小鼠的异位神经元连接和PNN，PV神经元和PNN包裹PV神经元在各种感觉皮层区域和不同的出生后年龄的发展，这可能会导致一些皮质兴奋/抑制（E/I）与ASD的不平衡的变化。这些发现表明，在这种疾病的小鼠模型中，皮层区域的神经解剖学改变是ASD相关行为出现的基础。
Autism spectrum disorder (ASD) is associated with neurodevelopmental alterations, including atypical forebrain cellular organization. Mutations in several ASD-related genes often result in cerebral cortical anomalies, such as the abnormal developmental migration of excitatory pyramidal cells and the malformation of inhibitory neuronal circuitry. Notably here, mutations in the CNTNAP2 gene result in ectopic superficial cortical neurons stalled in lower cortical layers and alterations to the balance of cortical excitation and inhibition. However, the broader circuit-level implications of these findings have not been previously investigated. Therefore, we assessed whether ectopic cortical neurons in CNTNAP2 mutant mice form aberrant connections with higher-order thalamic nuclei, potentially accounting for some autistic behaviors, such as repetitive and hyperactive behaviors. Furthermore, we assessed whether the development of parvalbumin-positive (PV) cortical interneurons and their specialized matrix support structures, called perineuronal nets (PNNs), were altered in these mutant mice. We found alterations in both ectopic neuronal connectivity and in the development of PNNs, PV neurons and PNNs enwrapping PV neurons in various sensory cortical regions and at different postnatal ages in the CNTNAP2 mutant mice, which likely lead to some of the cortical excitation/inhibition (E/I) imbalance associated with ASD. These findings suggest neuroanatomical alterations in cortical regions that underlie the emergence of ASD-related behaviors in this mouse model of the disorder.
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