Interneuron NMDA Receptor Ablation Induces Hippocampus- Prefrontal Cortex Functional Hypoconnectivity after Adolescence in a Mouse Model of Schizophrenia
Interneuron NMDA Receptor Ablation Induces Hippocampus- Prefrontal Cortex Functional Hypoconnectivity after Adolescence in a Mouse Model of Schizophrenia
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DOI：
10.1523/jneurosci.1897-19.2020
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发表时间：
2020-04-15
影响因子：
5.3
通讯作者：
Belforte, Juan E.
中科院分区：
文献类型：
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作者：
Alvarez, Rodrigo J.;Pafundo, Diego E.;Belforte, Juan E.
虽然精神分裂症的病因仍然是未知的，但它被认为是一种神经发育障碍，是遗传脆弱性和环境损伤相互作用的结果。虽然精神分裂症的病理生理学仍不清楚，但尸检研究指出，皮质中间神经元功能障碍是一个核心因素。已经表明，精神分裂症中小清蛋白阳性中间神经元的改变是通过NMDAR的信号传导缺陷的结果。动物研究表明，出生后早期消融皮质边缘中间神经元中的NMDAR诱导与精神分裂症相关的神经生化、生理、行为和流行病学表型。值得注意的是，行为异常仅在动物在青春期完成成熟后出现，如果NMDAR在成年期被删除，则不存在。这表明中间神经元功能障碍必须与发育相互作用才能影响行为。在这里，我们评估在体内如何早期NMDAR消融皮质边缘中间神经元影响mPFC和腹侧海马功能连接之前和之后的青春期。在幼年雄性小鼠中，NMDAR消融导致几种病理生理学特征，包括皮质活动增加和对局部γ和远端海马θ节律的夹带减少。此外，成年雄性KO小鼠表现出腹侧海马-mPFC-诱发电位降低和增强的低频刺激LTD的途径，这表明有一个功能性断开成年KO小鼠的两个结构之间。我们的研究结果表明，中间神经元的早期遗传异常可以与青春期的出生后发育相互作用，引发与精神分裂症相关的病理生理机制，超过单独由NMDAR中间神经元功能减退引起的机制。
Although the etiology of schizophrenia is still unknown, it is accepted to be a neurodevelopmental disorder that results from the interaction of genetic vulnerabilities and environmental insults. Although schizophrenia's pathophysiology is still unclear, postmortem studies point toward a dysfunction of cortical interneurons as a central element. It has been suggested that alterations in parvalbumin-positive interneurons in schizophrenia are the consequence of a deficient signaling through NMDARs. Animal studies demonstrated that early postnatal ablation of the NMDAR in corticolimbic interneurons induces neurobiochemical, physiological, behavioral, and epidemiological phenotypes related to schizophrenia. Notably, the behavioral abnormalities emerge only after animals complete their maturation during adolescence and are absent if the NMDAR is deleted during adulthood. This suggests that interneuron dysfunction must interact with development to impact on behavior. Here, we assess in vivo how an early NMDAR ablation in corticolimbic interneurons impacts on mPFC and ventral hippocampus functional connectivity before and after adolescence. In juvenile male mice, NMDAR ablation results in several pathophysiological traits, including increased cortical activity and decreased entrainment to local gamma and distal hippocampal theta rhythms. In addition, adult male KO mice showed reduced ventral hippocampus-mPFC-evoked potentials and an augmented low-frequency stimulation LTD of the pathway, suggesting that there is a functional disconnection between both structures in adult KO mice. Our results demonstrate that early genetic abnormalities in interneurons can interact with postnatal development during adolescence, triggering pathophysiological mechanisms related to schizophrenia that exceed those caused by NMDAR interneuron hypofunction alone.