Monoaminergic regulation of prefrontal cortex inhibition during adolescence

描述(由申请人提供)：本提案的总体目标是确定前额叶皮质(PFC)神经元间回路的年龄相关调制的细胞机制。这种发育调节与精神分裂症的病理生理学高度相关，因为趋同的发现强调发育过程中神经元间的缺陷是这种疾病的潜在基础。然而，神经回路的早期发育失调如何影响皮质神经元间成熟的发育轨迹之间的联系仍不清楚。PFC是研究皮质抑制电路作用的好地方，因为PFC在工作记忆和决策方面发挥着重要作用，这些功能在精神分裂症中变得受损。我们最近发表的工作和初步研究表明，PFC神经元间的活动在青春期后增强。这种青春期后/青春期晚期的易化被认为与中皮质多巴胺系统的延迟成熟以及谷氨酸能驱动对这些GABA能中间神经元的易化有关。如果在发育过程中，这种神经元间的活性没有增强，PFC抑制控制将在成熟时改变。在精神分裂症和某些精神障碍中观察到的青春期周围过渡期间，这种损害对于PFC认知缺陷的发生是重要的。我们的中心假设是，PFC GABA神经元间功能的正常成熟源于两个同时发生的青春期晚期事件：(1)PFC间神经元上谷氨酸能驱动的增强；(2)突触后钙依赖的信号机制的获得，使神经元间对多巴胺的反应增加。因此，提出这项工作的基本原理是，PFC谷氨酸能输入的发育失调将足以改变前额叶神经元间功能的正常轨迹。目的1将确定有助于促进PFC神经元间活动发育的细胞机制。目的2将确定PFC神经元间功能的发育促进对中皮质诱导的同步活动的影响。目的3将确定有助于促进青春期晚期PFC GABA中间神经元活性的谷氨酸能输入的解剖学来源。我们的预测是，突触前谷氨酸能驱动对PFC中间神经元的易化决定了多巴胺控制PFC抑制传递的正常成熟。我们的结果将导致新的生理学和分子策略，以靶向PFC神经元间成熟的突触前机制，这将增加皮质抑制传递。 公共卫生相关性：这项建议旨在确定大脑皮质活动依赖年龄调节的细胞机制，重点放在前额叶皮质神经元间回路上。这种发育调节与精神分裂症的病理生理学高度相关，因为趋同的发现强调发育过程中神经元间的缺陷是这种疾病的潜在基础。因此，成功完成拟议的应用将导致发现概念、药理学和生理学工具，能够剖析正常和异常青春期过渡到成年期的抑制网络的作用，并提供关于精神分裂症认知症状如何在青春期后期出现的关键知识。

DESCRIPTION (provided by applicant): The overall objective of this proposal is to determine the cellular mechanisms underlying the age-dependent modulation of prefrontal cortical (PFC) interneuronal circuits. Such developmental regulation is highly relevant to the pathophysiology of schizophrenia since converging findings stress interneuron deficits during development as a potential basis for this disorder. However, the link between how an early developmental dysregulation of neural circuits affects the developmental trajectory of cortical interneuron maturation remains unknown. The PFC is a good site for studying the role of cortical inhibitory circuits, since the PFC plays an important role in working memory and decision-making, functions that become impaired in schizophrenia. Our recently published work and preliminary studies indicate that PFC interneuronal activity is enhanced after puberty. This postpubertal/late adolescent facilitation is thought to be related to the delayed maturation of the mesocortical dopamine system and the enhanced facilitation of glutamatergic drive onto these GABAergic interneurons. If during development, such interneuronal activity does not become enhanced, PFC inhibitory control will be altered at maturity. Such impairment would be important for the onset of PFC cognitive deficits during the periadolescent transition as observed in schizophrenia and certain psychiatric disorders. Our central hypothesis is that normal maturation of PFC GABA interneuronal function results from two concurrent late adolescent events: (i) augmentation of glutamatergic drive onto PFC interneurons; (ii) acquisition of postsynaptic Ca2+dependent signaling mechanisms that enable the increased interneuron response to dopamine. Thus, the rationale for the proposed work is that the developmental dysregulation of glutamatergic inputs to the PFC will be sufficient to alter the normal trajectory of prefrontal interneuronal function. Aim 1 will determine the cellular mechanisms that contribute to the developmental facilitation of PFC interneuronal activity. Aim 2 will determine the impact of the developmental facilitation of PFC interneuronal function on mesocortical-induced synchronous activity. Aim 3 will determine the anatomical origin of glutamatergic inputs that contribute to the late-adolescent facilitation of PFC GABA interneuron activity. Our prediction is that presynaptic facilitation of glutamatergic drive onto PFC interneurons dictates the normal maturation of dopamine control of PFC inhibitory transmission. Our results should lead to novel physiological and molecular strategies to target the presynaptic mechanisms underlying PFC interneuronal maturation that will increase cortical inhibitory transmission. PUBLIC HEALTH RELEVANCE: This proposal is aimed to determine the cellular mechanisms underlying the age-dependent modulation of cortical activity, with focus on prefrontal cortical interneuronal circuits. Such developmental regulation is highly relevant to the pathophysiology of schizophrenia since converging findings stress interneuron deficits during development as a potential basis for this disorder. Thus, successful completion of the proposed application should lead to the discovery of conceptual, pharmacological and physiological tools capable of dissecting the role of inhibitory network underlying normal and abnormal periadolescent transition to adulthood, and to provide critical knowledge on how cognitive symptoms in schizophrenia emerge late in adolescence.