Hippocampal CA2 sharp wave ripple oscillations in neuropsychiatric disease

患有精神分裂症和其他神经精神障碍的个体患有异常的社会行为， 几乎没有有效的治疗方法。在这里，我们的目标是深入了解大脑机制负责 这种功能障碍，重点是改变神经网络活动模式的作用， 脑刺激疗法我们主要研究Df（16）A+/-的社会记忆（SM）缺陷 人类22q11.2缺失综合征的小鼠模型，这是已知遗传风险最高的疾病之一。 精神分裂症的因素。我们在目前资助期间的研究表明，小鼠SM缺陷 结果，至少部分，从海马CA 2锥体神经元的异常活动，这是已知的， 对SM来说至关重要在细胞水平上，Df（16）A+/-小鼠中的CA 2锥体神经元由于细胞外基质的存在而超极化。 TREK-1静息K+电流增加，导致兴奋性降低。我们的体内记录显示， 野生型，而不是Df（16）A+/-小鼠，CA 2锥体神经元作为社会新奇感的检测器，CA 2放电 对一只新老鼠和一只熟悉的老鼠有不同的反应。特别有趣的是，我们发现， 和/或TREK-1的遗传抑制可以拯救Df（16）A+/-小鼠中编码社会新奇的SM和CA 2。 最后，我们发现Mirta 22/Emc 10的上调，Mirta 22/Emc 10是一种膜蛋白运输的调节因子，它被去表达。 在Df（16）A+/-小鼠中由于microRNA失调而受到抑制，是22q11.2的关键分子结果。 导致异常SM的缺失。在这里，我们的目标是提供更深入的了解如何改变CA 2 功能会产生一种异常形式的脑震荡，称为尖波波纹， 来巩固记忆我们将研究异常的尖波波纹如何影响SM，以及是否 通过光遗传学脑刺激恢复正常的尖波波纹可以挽救SM。作为尖波 Df（16）A+/-小鼠的CA 1中的波纹是异常的，并且当CA 1中出现显著比例的尖波波纹时， 在CA 2区，我们推测Df（16）A+/-小鼠SM的缺陷可能是由于异常的CA 2尖波 涟漪此外，我们还发现，使用适当形状的光遗传学模式激活CA 2， 可以在野生型小鼠中触发正常SWRS的光可以在Df（16）A+/-小鼠中恢复正常SWRS，并且这 拯救SM最后，为了更深入地了解与细胞凋亡相关的分子变化之间的联系， 22q11.2基因缺失和脑功能改变，我们将探讨Mirta 22/Emc 10是否上调 CA 2功能障碍的基础，包括CA 2 TREK-1活性增加，异常社会编码和异常 尖锐的波纹通过这种方式，我们将提供一个统一的理解，将遗传，分子，细胞， 网络和行为机制，有助于与人类相关的社会认知功能障碍 与神经精神疾病有关的基因突变，目的是确定新的治疗方法 基于脑刺激范例的合理设计。

Individuals with schizophrenia and other neuropsychiatric disorders suffer from abnormal social behaviors, for which there are few effective treatments. Here we aim to gain insight into the brain mechanisms responsible for such dysfunction, focusing on the role of altered patterns of neural network activity that may be amenable to treatment with brain stimulation paradigms. We focus on the social memory (SM) deficits in the Df(16)A+/- mouse model of the human 22q11.2 deletion syndrome, which confers one of the highest known genetic risk factors for schizophrenia. Our studies during the present funding period demonstrate that the mouse SM deficit results, at least in part, from abnormal activity of hippocampal CA2 pyramidal neurons, which are known to be critical for SM. At the cellular level, CA2 pyramidal neurons in the Df(16)A+/- mice are hyperpolarized due to an increase in the TREK-1 resting K+ current, leading to decreased excitability. Our in vivo recordings show that in wild-type, but not Df(16)A+/- mice, CA2 pyramidal neurons act as detector of social novelty, with CA2 firing differentially responding to a novel versus familiar mouse. Of particular interest, we found that pharmacological and/or genetic inhibition of TREK-1 could rescue both SM and CA2 coding for social novelty in Df(16)A+/- mice. Finally we found that upregulation of Mirta22/Emc10, a regulator of membrane protein trafficking that is de- repressed in Df(16)A+/- mice due to microRNA dysregulation, is a key molecular consequence of the 22q11.2 deletion that contributes to abnormal SM. Here we aim to provide deeper insight into how alterations in CA2 function produce an abnormal form of brain oscillations known as sharp-wave ripples, events that are critical for memory consolidation. We will examine how abnormal sharp-wave ripples affect SM, and whether reinstatement of normal sharp-wave ripples by optogenetic brain stimulation can rescue SM. As sharp-wave ripples are abnormal in CA1 of Df(16)A+/- mice, and as a significant fraction of sharp-wave ripples in CA1 arise in CA2, we hypothesize that the deficit in SM in Df(16)A+/- mice may result from abnormal CA2 sharp-wave ripples. Furthermore, we surmise that optogenetic activation of CA2 using appropriately shaped patterns of light that can trigger normal SWRs in wild-type mice may reinstate normal SWRS in Df(16)A+/- mice, and this may rescue SM. Finally to gain deeper insight into the link between molecular changes associated with the 22q11.2 genetic deletion and altered brain function, we will explore whether Mirta22/Emc10 upregulation underlies CA2 dysfunction, including increased CA2 TREK-1 activity, abnormal social coding and abnormal sharp-wave ripples. In this way we will provide a unified understanding linking the genetic, molecular, cellular, network, and behavioral mechanisms that contribute to social cognitive dysfunction associated with a human genetic mutation linked to neuropsychiatric disease, with the aim of identifying novel approaches to treatment based on the rational design of brain stimulation paradigms.