Endogenous Kynurenic Acid Modulates Prefrontal ACh Levels and Cognitive Behavior

描述（由申请人提供）：精神分裂症（SZ）是一种使人衰弱的精神障碍，在前额叶皮层（PFC）中具有显著和复杂的病理生理学。这种皮质病理学的几个方面与执行功能的缺陷有关，例如工作记忆，注意力和认知灵活性。更深入地了解导致这些认知障碍的神经化学机制至关重要，因为传统的抗精神病药物在缓解这些障碍方面并不特别有效，而且这些缺陷的严重程度可以预测患者融入社会的能力。PFC中17种烟碱受体（17 nAChR）的活性与许多测量执行认知功能的行为任务的表现呈正相关。相反，皮质17nAChRs的失调已牵连在SZ的病因。犬尿烯酸（KYNA）是一种星形胶质细胞衍生的神经调节剂，在内源性浓度下，可抑制多个大脑区域（包括PFC）的17 nAChR活性。精神分裂症患者的PFC中KYNA水平升高，这种升高不是次要的抗精神病药物。该项目旨在确定KYNA在调节PFC中的基础和刺激谷氨酸和乙酰胆碱（ACh）水平以及在介导前额叶介导的认知行为（感知定势转换）中的作用。我们在大鼠中的初步数据表明，KYNA的内源性水平的波动调节PFC中谷氨酸和ACh的水平。拟议的实验将使用互补的生物化学，药理学和行为方法，以及两个有经验的PI的协同专业知识，以评估KYNA，ACh和谷氨酸在大鼠PFC中。目的#1将利用体内微透析来测试PFC内内源性KYNA水平的波动在17nAChR活性的基础水平的条件下影响谷氨酸和ACh水平的假设。我们还将确定这些影响，假设，是否可以追溯到KYNA的能力，拮抗17 nAChR和是否KYNA相关的调制ACh水平介导的局部谷氨酸。目标#2将确定，作为任务执行大鼠后续目标的前奏，KYNA在激活17 nAChR的两种条件下（中枢给药药物和行为条件反射范例）保留调节前额叶谷氨酸和ACh释放的能力的程度。目的#3将这些神经化学研究扩展到认知行为领域，并将测试皮质KYNA水平升高选择性损害大鼠执行感知集转移任务的能力的假设，这取决于PFC中神经传递的完整性。我们还将确定胆碱能和神经元能功能减弱在KYNA诱导的行为缺陷中的相对作用。这与SZ的病理生理学尤其相关，其与PFC中的过量KYNA水平、异常皮质多巴胺能和烟碱能传递以及设置转换任务中的明显损伤相关。最后，由于在SZ中观察到皮质KYNA水平的长期升高，我们将在目标#4中研究脑KYNA水平持续增加的生化和功能后果。这些慢性效应将在对照动物和用典型（氟哌啶醇）或非典型（氯氮平）精神抑制药物联合靶向17 nAChR的连续治疗与临床使用的认知增强药物（加兰他敏）治疗的大鼠中进行评价。总的来说，拟议的实验将测试新的假设，即星形胶质细胞衍生的KYNA水平的波动有效地调节皮质神经传递和前额叶介导的认知行为。我们将利用这些发现来生成一个实验平台，用于测试基于KYNA的治疗在缓解SZ中所见的认知缺陷方面的治疗效果。

DESCRIPTION (provided by applicant): Schizophrenia (SZ) is a debilitating mental disorder with significant and complex pathophysiology in the prefrontal cortex (PFC). Several aspects of this cortical pathology have been linked to deficits in executive functions such as working memory, attention, and cognitive flexibility. A more thorough understanding of the neurochemical mechanisms contributing to these cognitive disorders is critical, as conventional antipsychotics are not particularly effective in alleviating these impairments, and since the severity of these deficits is predictive of the patient's ability to integrate into society. The activity of 17 nicotinic receptors (17nAChR) in the PFC has been positively linked to performance in a number of behavioral tasks that measure executive cognitive functions. Conversely, dysregulation of cortical 17nAChRs has been implicated in the etiology of SZ. Kynurenic acid (KYNA) is an astrocyte-derived neuromodulator that, at endogenous concentrations, inhibits 17nAChR activity in several brain regions, including the PFC. KYNA levels are elevated in the PFC of individuals with schizophrenia, and this increase is not secondary to antipsychotic medication. This project is designed to define the role of KYNA in the modulation of basal and stimulated glutamate and acetylcholine (ACh) levels in the PFC and in the mediation of a prefrontally- mediated cognitive behavior (perceptual set-shifting). Our preliminary data in rats demonstrate that fluctuations in the endogenous levels of KYNA modulate levels of glutamate and ACh in the PFC. The proposed experiments will use complementary biochemical, pharmacological and behavioral methods, and the synergistic expertise of two experienced PIs, to evaluate key chemical events and functional implications of this link between KYNA, ACh and glutamate in the rat PFC. Aim #1 will utilize in vivo microdialysis to test the hypothesis that fluctuations in endogenous KYNA levels within the PFC influence glutamate and ACh levels under conditions of basal levels of 17nAChR activity. We will also determine whether these effects, as hypothesized, can be traced to KYNA's ability to antagonize the 17nAChR and whether the KYNA-related modulation of ACh levels is mediated by local glutamate. Aim #2 will determine, as a prelude to subsequent aims in task-performing rats, the extent to which KYNA retains the ability to modulate prefrontal glutamate and ACh release under two conditions that activate the 17nAChR (a centrally-administered drug and a behavioral conditioning paradigm). Aim #3 extends these neurochemical studies to the realm of cognitive behavior and will test the hypothesis that elevations in cortical KYNA levels selectively impair the ability of rats to perform in a perceptual set-shifting task, which is dependent upon the integrity of neurotransmission in the PFC. We will also determine the relative roles of diminished cholinergic and glutamatergic function in this KYNA-induced behavioral deficit. This is especially relevant to the pathophysiology of SZ which is associated with excessive KYNA levels in the PFC, abnormal cortical glutamatergic and nicotinergic transmission, and pronounced impairments in set- shifting tasks. Finally, since prolonged elevations of cortical KYNA levels are seen in SZ, we will, in Aim #4, study the biochemical and functional consequences of persistent increases in brain KYNA levels. These chronic effects will be evaluated both in control animals and in rats treated with typical (haloperidol) or atypical (clozapine) neuroleptic drugs in combination with an adjunctive therapy targeting the 17nAChR with a clinically used cognition-enhancing drug (galantamine). Collectively, the proposed experiments will test the new hypothesis that fluctuations in astrocyte-derived KYNA levels potently modulate cortical neurotransmission and prefrontally-mediated cognitive behavior. We will use these findings to generate an experimental platform for testing the therapeutic efficacy of KYNA-based treatments in alleviating the cognitive deficits seen in SZ.