Neonatal Seizure Therapy and Susceptibility to Schizophrenia

新生儿癫痫治疗和精神分裂症易感性

• 批准号: 7489277
• 负责人: ALEXEI D KONDRATYEV
• 金额: $ 19.74万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-26 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7489277
• 关键词: Affect; Animal Model; Antiepileptic Agents; Apoptotic; Behavioral; Brain; Brain region; Cell Death; Cessation of life; Collaborations; Comorbidity; Development; Disease; Dopamine; Drug Exposure; Epidemiologic Studies; Epilepsy; Febrile Convulsions; Foundations; Future; Hand; Hippocampus (Brain); Impact Seizures; Impaired cognition; Infant; Learning; Lesion; Life; Longitudinal Studies; Memory; Mental disorders; Modeling; Neonatal; Neurons; Numbers; Outcome; Pharmaceutical Preparations; Pharmacotherapy; Predisposition; Pregnant Women; Premature Infant; Probability; Psychotic Disorders; Public Health; Purpose; Rattus; Recording of previous events; Recurrence; Research Personnel; Risk; Risk Factors; Schizophrenia; Seizures; Social Interaction; Solid; Staging; Testing; Time; Week; Work; critical developmental period; experience; forging; neonate; neuron apoptosis; neuron loss; postnatal

DESCRIPTION (provided by applicant): The exploratory studies proposed in this R21 aim to examine the as yet unexplored interrelationship between seizure disorders and mental illness in a neurodevelopmental animal model of schizpohrenia. Whether epilepsy or seizures in neonates, or in pre-term infants, increase predisposition to subsequent psychiatric disorders had been a matter of some controversy. Recent epidemiological studies indicate that a history of febrile seizures or epilepsy is associated with a significantly increased risk for schizophrenia. This raises the possibility that seizures themselves during a critical period contribute to the expression of schizophrenia. However, because seizure disorders are treated with antiepileptic drugs (AEDs), AED treatment is an important confounding factor which may adversely affect psychiatric outcomes, especially when given during brain maturation. Treatment with certain AEDs during early postnatal brain development triggers apoptotic neuronal cell death in several brain regions, raising the possibility that these drugs can alter neurodevelopmental outcomes. The only way to disentangle the potential adverse impact of seizures from the adverse impact of AED therapy is to analyze these variables independently in an appropriate animal model. The recently characterized neurodevelopmental lesion-induced model of schizophrenia in the rat is ideally suited for this purpose because the critical period for induction of the focal lesion in the ventral hippocampus (Vh) is the same developmental period that is most vulnerable to AED-induced neuronal apoptosis. Our general working hypothesis is that AEDs that promote apoptotic neuronal death during the second postnatal week in the rat will augment the lesion-induced behavioral and cognitive disturbances later in life. At the same time, we predict that AEDs that we have recently identified as devoid of cell death-promoting actions in infant rats will not exacerbate the effects of the lesion. Moreover, we will also determine whether induction of recurrent seizures influences the adverse behavioral outcomes of the neonatal Vh lesion. By examining the interactions between the Vh lesions and AED exposure, on the one hand, and between Vh lesions and seizure experience on the other, we will determine whether one or both of these potential risk factors increase the probability of adverse psychiatric outcomes, as reflected in a battery of tests evaluating activity, social interactions, learning and memory, and the responsiveness to a challenge with a dopamine stimulant. This information will lay a solid foundation for future longer-term studies of the factor(s) responsible for the comorbidity between seizure disorders and schizophrenia. A unique inter-institutional collaboration between investigators with expertise in epilepsy, on the one hand, and expertise in psychiatric disorders on the other, will be forged to achieve the proposed specific aims. Relevance to Public Health: Epilepsy and seizures in early stages of postnatal brain development, or in premature infants, increase predisposition to a number of psychiatric disorders including schizophrenia. Because seizures are treated with anti-epileptic drugs (AEDs), there is a serious potential for the AED treatment to be a contributing factor to such predisposition. In the proposed study we will examine whether AEDs and/or repeated seizure exposure increase predisposition to psychosis in the neurodevelopmental animal model of schizophrenia. This study also aims at identifying AEDs that will not predispose the neonates and pregnant women afflicted with seizures to schizophrenia- like disorders.

描述（由申请人提供）：本 R21 中提出的探索性研究旨在检查精神分裂症神经发育动物模型中癫痫发作障碍和精神疾病之间尚未探索的相互关系。无论是新生儿或早产儿的癫痫或癫痫发作，是否会增加随后精神疾病的易感性一直是一个有争议的问题。最近的流行病学研究表明，热性惊厥或癫痫病史与精神分裂症风险显着增加相关。这增加了关键时期癫痫发作本身导致精神分裂症表现的可能性。然而，由于癫痫病是用抗癫痫药物 (AED) 治疗的，因此 AED 治疗是一个重要的混杂因素，可能会对精神结局产生不利影响，尤其是在大脑成熟期间进行治疗时。在产后早期大脑发育过程中使用某些 AED 治疗会引发多个大脑区域的神经元细胞凋亡，从而增加了这些药物改变神经发育结果的可能性。将癫痫发作的潜在不利影响与 AED 治疗的不利影响区分开来的唯一方法是在适当的动物模型中独立分析这些变量。最近描述的大鼠精神分裂症神经发育损伤诱发模型非常适合此目的，因为腹侧海马 (Vh) 中诱发局灶性损伤的关键期与最容易受到 AED 诱发的神经元损伤的发育期相同。细胞凋亡。我们的一般工作假设是，在大鼠出生后第二周促进细胞凋亡的神经元死亡的 AED 将在以后的生活中加剧病变引起的行为和认知障碍。与此同时，我们预测，我们最近发现的对幼年大鼠缺乏细胞死亡促进作用的 AED 不会加剧病变的影响。此外，我们还将确定反复发作的诱发是否会影响新生儿 Vh 病变的不良行为结果。通过一方面检查 Vh 病变与 AED 暴露之间的相互作用，另一方面检查 Vh 病变与癫痫发作经历之间的相互作用，我们将确定这些潜在危险因素中的一个或两个是否会增加不良精神结果的可能性，如所反映的在一系列测试中评估活动、社交互动、学习和记忆以及对多巴胺兴奋剂挑战的反应能力。这些信息将为未来对导致癫痫症和精神分裂症之间共病的因素进行长期研究奠定坚实的基础。一方面具有癫痫专业知识，另一方面具有精神疾病专业知识的研究人员之间将建立独特的机构间合作，以实现拟议的具体目标。与公共卫生的相关性：出生后大脑发育早期或早产儿的癫痫和癫痫发作会增加罹患包括精神分裂症在内的许多精神疾病的倾向。由于癫痫发作是用抗癫痫药物 (AED) 治疗的，因此 AED 治疗很可能成为导致这种倾向的一个因素。在拟议的研究中，我们将检查 AED 和/或反复癫痫发作是否会增加精神分裂症神经发育动物模型中精神病的易感性。这项研究还旨在确定不会使患有癫痫发作的新生儿和孕妇患上精神分裂症样疾病的 AED。