Anterior thalamic dysfunction underlies cognitive deficits in a subset of neuropsychiatric disease models.
Anterior thalamic dysfunction underlies cognitive deficits in a subset of neuropsychiatric disease models.
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DOI：
10.1016/j.neuron.2021.06.005
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发表时间：
2021-08-18
期刊：
影响因子：
16.2
通讯作者：
Feng G
中科院分区：
文献类型：
--
作者：
Roy DS;Zhang Y;Aida T;Choi S;Chen Q;Hou Y;Lea NE;Skaggs KM;Quay JC;Liew M;Maisano H;Le V;Jones C;Xu J;Kong D;Sullivan HA;Saunders A;McCarroll SA;Wickersham IR;Feng G
神经精神障碍通常伴有认知障碍/智力残疾（ID）。目前尚不清楚这些衰弱性损伤背后是否存在趋同机制。我们发现许多自闭症和精神分裂症风险基因在丘脑前核的前嗅（AD）分支中表达，该分支与学习和记忆结构具有相互联系。CRISPR-Cas9在AD丘脑中选择性敲低多个风险基因导致记忆缺陷。虽然AD是上下文记忆编码所必需的，但邻近的前腹侧（AV）细分调节记忆特异性。AD和AV的这些不同功能是通过它们在脾后皮层的投射介导的，并使用不同的机制。此外，AD中自闭症和精神分裂症风险基因PTCHD1、YWHAG或HERC1的敲除会导致神经元的高兴奋性，而高兴奋性的正常化可以挽救这些模型中的记忆缺陷。本研究确定了神经精神疾病模型子集中认知缺陷的趋同细胞到电路机制。神经精神障碍常伴有认知障碍。Roy等人报告说，从前丘脑中敲除几个自闭症和精神分裂症风险基因会导致过度兴奋和认知缺陷。高兴奋性的正常化拯救了各模型的认知缺陷，揭示了认知缺陷背后的趋同机制。
Neuropsychiatric disorders are often accompanied by cognitive impairments/intellectual disability (ID). It is not clear whether there are converging mechanisms underlying these debilitating impairments. We found that many autism and schizophrenia risk genes are expressed in the anterodorsal (AD) subdivision of anterior thalamic nuclei, which has reciprocal connectivity with learning and memory structures. CRISPR-Cas9 knockdown of multiple risk genes selectively in AD thalamus led to memory deficits. While AD is necessary for contextual memory encoding, the neighboring anteroventral (AV) subdivision regulates memory specificity. These distinct functions of AD and AV are mediated through their projections to retrosplenial cortex, using differential mechanisms. Furthermore, knockdown of autism and schizophrenia risk genes PTCHD1, YWHAG, or HERC1 from AD led to neuronal hyperexcitability, and normalization of hyperexcitability rescued memory deficits in these models. This study identifies converging cellular to circuit mechanisms underlying cognitive deficits in a subset of neuropsychiatric disease models. Neuropsychiatric disorders are often accompanied by cognitive impairments. Roy et al. report that the knockdown of several autism and schizophrenia risk genes from anterodorsal thalamus leads to hyperexcitability and cognitive deficits. Normalization of hyperexcitability rescues cognitive deficits across models, revealing a converging mechanism underlying cognitive deficits.
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影响因子：
64.5
作者：
Saunders A;Macosko EZ;Wysoker A;Goldman M;Krienen FM;de Rivera H;Bien E;Baum M;Bortolin L;Wang S;Goeva A;Nemesh J;Kamitaki N;Brumbaugh S;Kulp D;McCarroll SA
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影响因子：
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通讯作者：
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影响因子：
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作者：
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