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人患有异常的社会行为，例如 这方面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，集中在改变的神经网络活动模式的作用，可能是服从于 脑刺激模式治疗。我们关注的是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，这是已知的最高遗传风险之一 导致精神分裂症的因素。我们在本资助期间的研究表明，小鼠的SM赤字 结果，至少部分是由于海马CA2区锥体神经元的异常活动，这是已知的 对SM至关重要。在细胞水平上，DF(16)A/-小鼠CA2锥体神经元超极化是由于 Trek-1静息K电流增加，导致兴奋性降低。我们的活体记录显示，在 野生型，但不是DF(16)A/-小鼠，CA2锥体神经元作为社会新颖性的检测器，与CA2放电 对新奇的鼠标和熟悉的鼠标做出不同的反应。特别有趣的是，我们发现从药理上讲 和/或基因抑制Trek-1可以挽救编码社会新颖性的SM和CA2在DF(16)A/-小鼠中的表达。 最后我们发现，膜蛋白运输的调节因子Mirta22/Emc10的表达上调。 在df(16)A/-小鼠中由于microRNA失调而被抑制，是22q11.2的一个关键的分子后果 导致SM异常的缺失。在这里，我们旨在更深入地了解CA2中的变化 功能会产生一种异常形式的大脑振荡，称为尖波涟漪，这是至关重要的事件 用来巩固记忆。我们将研究异常尖锐的波纹如何影响SM，以及是否 通过光遗传脑刺激恢复正常的尖波纹波可以挽救SM。作为锐利的波 DF(16)A/-小鼠CA1区波纹异常，且随着CA1区锐波波纹的显著增加 在CA2中，我们假设DF(16)A/-小鼠SM的缺陷可能是由于CA2尖波的异常所致 涟漪。此外，我们推测，CA2的光遗传激活使用适当形状的 能够在野生型小鼠中触发正常SWR的光可能会恢复DF(16)A/-小鼠的正常SWR，而这 可能会救出SM。最后，为了更深入地了解与 22q11.2基因缺失和脑功能改变，我们将探讨Mirta22/Emc10是否上调 CA2功能障碍的基础，包括CA2 Trek-1活性增加，社会编码异常和异常 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、 与人类相关的社会认知功能障碍的网络和行为机制 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 基于脑刺激范式的合理设计。

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.