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层（PFC）神经元间回路年龄依赖性调制的细胞机制。这种发育调节是高度相关的精神分裂症的病理生理学，因为收敛的研究结果应力interneuron赤字在发展过程中作为一个潜在的基础，这种疾病。然而，神经回路的早期发育失调如何影响皮质中间神经元成熟的发育轨迹之间的联系仍然未知。前额叶皮层是研究皮层抑制回路作用的好地方，因为前额叶皮层在工作记忆和决策中起着重要作用，而这些功能在精神分裂症中会受损。我们最近发表的工作和初步研究表明，PFC神经元间的活动增强青春期后。这种青春期后/青春期后期的易化被认为与中皮层多巴胺系统的成熟延迟和对这些GABA能中间神经元的多巴胺能驱动的增强易化有关。如果在发育过程中，这种神经元间活动没有增强，PFC抑制控制将在成熟时改变。这种损害将是重要的PFC认知功能障碍的发病在青春期过渡期的精神分裂症和某些精神疾病中观察到。我们的中心假设是，PFC GABA中间神经元功能的正常成熟是由两个并发的青春期晚期事件引起的：（i）PFC中间神经元的多巴胺能驱动增强;（ii）突触后Ca 2+依赖性信号传导机制的获得，使中间神经元对多巴胺的反应增加。因此，拟议的工作的理由是，发育失调的前脑前额叶皮层的神经元输入将足以改变正常的轨迹，前额叶神经元功能。目的1将确定有助于PFC神经元间活动的发育促进的细胞机制。目的2将确定PFC中间神经元功能的发育易化对中皮层诱导的同步活动的影响。目的3将确定有助于青少年后期PFC GABA中间神经元活动的易化的海马能输入的解剖学起源。我们的预测是，突触前促进PFC中间神经元的多巴胺能驱动决定了PFC抑制性传递的多巴胺控制的正常成熟。我们的研究结果将导致新的生理和分子策略，以针对突触前机制的PFC神经元间的成熟，这将增加皮层抑制性传输。 公共卫生相关性：本研究的目的是确定年龄依赖性的皮层活动调制的细胞机制，重点是前额叶皮层神经元间回路。这种发育调节是高度相关的精神分裂症的病理生理学，因为收敛的研究结果应力interneuron赤字在发展过程中作为一个潜在的基础，这种疾病。因此，成功完成拟议的应用程序应导致发现的概念，药理学和生理学的工具，能够解剖的作用，抑制网络潜在的正常和异常的青春期过渡到成年，并提供关键知识，精神分裂症的认知症状出现在青春期后期。

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.