Neonatal Seizure Therapy and Susceptibility to Schizophrenia

描述（由申请方提供）：本R21中提出的探索性研究旨在检查癫痫发作障碍和精神疾病之间尚未探索的神经发育性癫痫动物模型中的相互关系。无论是新生儿还是早产儿的癫痫或癫痫发作，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，热性惊厥或癫痫史与精神分裂症的风险显著增加有关。这就提出了一种可能性，即癫痫发作本身在一个关键时期有助于精神分裂症的表达。然而，由于癫痫发作疾病是用抗癫痫药物（AED）治疗的，AED治疗是一个重要的混杂因素，可能会对精神疾病的结局产生不利影响，特别是在大脑成熟期间给予AED时。在出生后早期脑发育过程中使用某些AEDs治疗会引发几个脑区的神经元细胞凋亡，这增加了这些药物可以改变神经发育结果的可能性。将癫痫发作的潜在不良影响与AED治疗的不良影响分开的唯一方法是在适当的动物模型中独立分析这些变量。最近的特点是神经发育损伤诱导的精神分裂症大鼠模型是理想的适合于此目的，因为在腹侧海马（Vh）的局灶性病变的诱导的关键时期是相同的发展时期，最容易受到AED诱导的神经元凋亡。我们的一般工作假设是，AED，促进凋亡神经元死亡在出生后第二周的大鼠将增加病变诱导的行为和认知障碍以后的生活。与此同时，我们预测，我们最近确定为缺乏细胞死亡促进行动的AED在幼鼠不会加剧病变的影响。此外，我们还将确定是否诱导复发性癫痫发作影响新生儿Vh病变的不良行为结果。通过检查Vh病变和AED暴露之间的相互作用，一方面，和Vh病变和癫痫发作的经验，另一方面，我们将确定是否这些潜在的风险因素之一或两者增加不良精神疾病结局的概率，反映在一组测试评估活动，社会交往，学习和记忆，以及与多巴胺兴奋剂的挑战的反应。这些信息将为今后长期研究癫痫发作与精神分裂症共病的相关因素奠定坚实的基础。一个独特的机构间合作的研究人员与癫痫的专业知识，一方面，在精神疾病的专业知识，将锻造，以实现拟议的具体目标。与公共卫生的相关性：在出生后大脑发育的早期阶段或在早产儿中的癫痫和癫痫发作增加了许多精神疾病包括精神分裂症的易感性。由于癫痫发作是用抗癫痫药物（AED）治疗的，因此AED治疗有可能成为这种倾向的一个促成因素。在拟议的研究中，我们将检查是否AEDs和/或反复癫痫发作暴露增加精神分裂症的神经发育动物模型的精神病易感性。本研究还旨在确定不会使患有癫痫发作的新生儿和孕妇易患精神分裂症样疾病的AED。

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.