Compartmentalization of Cyclic Nucleotide Signaling in the Ventral Hippocampus

描述(由申请人提供)：腹侧海马区环核苷酸信号的区隔社会缺陷是几种神经精神障碍的主要特征，如自闭症、精神分裂症和创伤后应激障碍，但目前还没有治疗这些症状的药物。如果没有可接受的社交行为，我们吸引配偶、从社会获取资源以及建立安全/可靠环境的能力就会受到严重损害。当一个人缺乏适当的社交行为时，他往往会受到排斥。社会孤立会恶化身心健康，增加死亡率，特别是在老年人和精神病患者中。更糟糕的是，社会孤立会进一步损害随后的社会行为--从而造成恶性循环。尽管适当的社会行为对于在一个人的环境中茁壮成长是至关重要的，但人们对控制社会行为的分子机制或社会经验如何改变这些信号通路知之甚少。这阻碍了针对社会缺陷的有效疗法的发展。为了开发有效的治疗方法，我们需要更好地了解社会缺陷背后的分子机制。磷酸二酯酶11A(PDE11A)是一种分解cAMP和cGMP的酶，可能是调节社会行为的重要分子机制。我们已经证明，缺乏PDE11A的小鼠不能正确地参与社会互动，也不能形成涉及社会线索的长期记忆。PDE11A几乎只在大脑的腹侧海马区表达，但在背侧海马区也有低水平的表达。基于这一分布，我们假设PDE11A4主要通过控制腹侧海马区的环核苷酸来调节社会行为。跨越这三个目标，我们采取了一种综合的实验方法，将体内的遗传操作与体内的行为测试以及体外分子和生化终点相结合。在具体目标1中，我们将确定PDE11A在哪里(VHIPP与背侧HIPP)以及何时(成年期与青春期)调节社会行为。在具体目标2中，我们将确定社会孤立如何改变PDE11A的区隔，从而损害随后的社会行为。在具体目标3中，我们将定义控制PDE11A亚细胞定位的信号。这些创新研究将为了解复杂社会行为的基本机制以及PDE11A在大脑中的功能和调节提供亟需的见解。靶向PDE11A可能是一种有选择地恢复特定大脑区域中调节社会行为的环核苷酸信号的方法，而不会影响其他地方的信号。这可能会缓解社会赤字，而不会产生不受欢迎的副作用。

DESCRIPTION (provided by applicant): Compartmentalization of Cyclic Nucleotide Signaling in the Ventral Hippocampus Social deficits are key features of several neuropsychiatric disorders, such as autism, schizophrenia, and PTSD, yet no medicines are available to remedy these symptoms. Without acceptable social behaviors, our ability to attract a mate, acquire resources from society, and establish a safe/secure environment is severely compromised. When an individual lacks proper social behaviors, one is often ostracized. Social isolation worsens mental and physical health and increases mortality, particularly among the elderly and mentally ill. To make matters worse, social isolation further impairs subsequent social behaviors-thus, creating a vicious cycle. Despite the fact that appropriate social behaviors are vital to thriving in one's environment, little is understood of the molecular mechanisms that control social behaviors or how social experiences modify these signaling pathways. This hampers the development of effective therapeutics for social deficits. To develop effective treatments, we need to better understand the molecular mechanisms that underlie social deficits. Phosphodiesterase 11A (PDE11A) is an enzyme that breaks down cAMP and cGMP, and PDE11A may be an important molecular mechanism for regulating social behavior. We have shown that mice that lack PDE11A do not properly engage in social interactions and fail to form long-term memories involving social cues. PDE11A is almost exclusively expressed in a small area of the brain called the ventral hippocampus, but there is also a low level of expression in the dorsal hippocampus. Based on this distribution, we hypothesize that PDE11A4 regulates social behavior primarily by controlling cyclic nucleotides in the ventral hippocampus. Across the 3 aims, we take an integrative experimental approach by coupling in vivo genetic manipulations with in vivo behavioral tests as well as ex vivo molecular and biochemical endpoints. In Specific Aim 1, we will determine where (VHIPP vs. dorsal HIPP) and when (adulthood vs. adolescence) PDE11A modulates social behaviors. In Specific Aim 2, we will identify how social isolation modifies PDE11A compartmentalization and, thus, impairs subsequent social behaviors. In Specific Aim 3, we will define the signals that control the subcellular localization of PDE11A. These innovative studies will provide much needed insight into the fundamental mechanisms of complex social behavior as well as the function and regulation of PDE11A in the brain. Targeting PDE11A may be a way to selectively restore cyclic nucleotide signaling in a specific brain region that regulates social behaviors, without affecting signaling elsewhere. This may relieve social deficits without causing unwanted side effects.