Ketamine Restores Thalamic-Prefrontal Cortex Functional Connectivity in a Mouse Model of Neurodevelopmental Disorder-Associated 2p16.3 Deletion
Ketamine Restores Thalamic-Prefrontal Cortex Functional Connectivity in a Mouse Model of Neurodevelopmental Disorder-Associated 2p16.3 Deletion
复制标题
DOI：
10.1093/cercor/bhz244
复制
发表时间：
2020-04-01
期刊：
影响因子：
3.7
通讯作者：
Dawson, Neil
中科院分区：
文献类型：
--
作者：
Hughes, Rebecca;Whittingham-Dowd, Jayde;Dawson, Neil
2p16.3缺失，包括杂合NEUREXIN 1（NRXN 1）缺失，显著增加了神经发育障碍的风险，包括自闭症和精神分裂症。我们对NRXN 1杂合性如何增加发生这些疾病的风险知之甚少，特别是在对大脑和神经递质系统功能以及大脑网络连接的影响方面。因此，在这里，我们描述了Nrxn 1 α杂合子小鼠（Nrxn 1 α（+/-）小鼠）的脑代谢和功能性脑网络连接，并评估了氯胺酮和β-苯丙胺对这些动物脑代谢的影响。我们发现，杂合子Nrxn 1 α缺失改变了自闭症和精神分裂症涉及的神经系统，包括丘脑，中脑边缘系统，并选择皮质区域的脑代谢。Nrxn 1 alpha杂合性也降低了功能性大脑网络的效率，通过丢失丘脑“丰富俱乐部”和前额叶皮层（PFC）枢纽连接，并通过减少丘脑-PFC和丘脑“丰富俱乐部”区域互连。亚麻醉氯胺酮给药使Nrxn 1 α（+/-）小鼠中存在的丘脑高代谢正常化，并使丘脑断开部分正常化，而对β-苯丙胺的脑代谢反应未改变。这些数据为杂合Nrxn 1 α缺失的系统水平影响以及这如何增加神经发育障碍的风险提供了新的见解。这些数据还表明，由杂合Nrxn 1 α缺失引起的丘脑功能障碍可能是NMDA受体依赖性的。
2p16.3 deletions, involving heterozygous NEUREXIN1 (NRXN1) deletion, dramatically increase the risk of developing neurodevelopmental disorders, including autism and schizophrenia. We have little understanding of how NRXN1 heterozygosity increases the risk of developing these disorders, particularly in terms of the impact on brain and neurotransmitter system function and brain network connectivity. Thus, here we characterize cerebral metabolism and functional brain network connectivity in Nrxn1 alpha heterozygous mice (Nrxn1 alpha(+/-) mice), and assess the impact of ketamine and dextro-amphetamine on cerebral metabolism in these animals. We show that heterozygous Nrxn1 alpha deletion alters cerebral metabolism in neural systems implicated in autism and schizophrenia including the thalamus, mesolimbic system, and select cortical regions. Nrxn1 alpha heterozygosity also reduces the efficiency of functional brain networks, through lost thalamic "rich club" and prefrontal cortex (PFC) hub connectivity and through reduced thalamic-PFC and thalamic "rich club" regional interconnectivity. Subanesthetic ketamine administration normalizes the thalamic hypermetabolism and partially normalizes thalamic disconnectivity present in Nrxn1 alpha (+/-) mice, while cerebral metabolic responses to dextro-amphetamine are unaltered. The data provide new insight into the systems-level impact of heterozygous Nrxn1 alpha deletion and how this increases the risk of developing neurodevelopmental disorders. The data also suggest that the thalamic dysfunction induced by heterozygous Nrxn1 alpha deletion may be NMDA receptor-dependent.