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皮质（PFC）神经元间回路的年龄依赖性调节的细胞机制。这种发育调节与精神分裂症的病理生理学高度相关，因为一些研究结果强调，发育过程中的中间神经元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层中间神经元成熟的发育轨迹之间的联系尚不清楚。由于PFC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，因此PFC是研究皮层抑制回路作用的一个很好的位点。我们最近发表的工作和初步研究表明，青春期后PFC神经元间活动增强。这种青春期后/青春期后期的促进作用被认为与中皮层多巴胺系统的延迟成熟和谷氨酸能驱动到这些gaba能中间神经元的促进作用增强有关。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发生改变。这种损伤对于在精神分裂症和某些精神疾病中观察到的青春期过渡期间PFC认知缺陷的发作很重要。我们的中心假设是PFC GABA神经元间功能的正常成熟是由两个并发的青春期后期事件引起的：(i)谷氨酸驱动到PFC中间神经元的增强；（ii）获得突触后Ca2+依赖的信号机制，使神经元间对多巴胺的反应增加。因此，提出的工作的基本原理是，谷氨酸能输入到PFC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脑皮层诱导的同步活动的影响。目的3将确定青春期后期促进PFC GABA中间神经元活动的谷氨酸能输入的解剖学起源。我们的预测是突触前谷氨酸驱动到PFC中间神经元的促进决定了多巴胺控制PFC抑制性传递的正常成熟。我们的研究结果将导致新的生理和分子策略，以PFC神经元间成熟的突触前机制为目标，这将增加皮层抑制传递。

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.