Neonatal Seizure Therapy and Susceptibility to Schizophrenia

描述(由申请人提供)：本R21中提出的探索性研究的目的是在精神分裂症的神经发育动物模型中检查迄今尚未探索的癫痫障碍和精神疾病之间的相互关系。在新生儿或早产儿中，癫痫或癫痫发作是否会增加随后精神障碍的易感性，一直存在一些争议。最近的流行病学研究表明，发热性癫痫或癫痫史与精神分裂症的风险显著增加有关。这增加了在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，由于癫痫发作障碍是用抗癫痫药物(AED)治疗的，AED治疗是一个重要的混杂因素，可能会对精神结果产生不利影响，特别是在大脑成熟期间给予AED治疗。在出生后大脑发育早期使用某些AEDs会引发几个脑区神经细胞的凋亡死亡，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。最近建立的神经发育损伤诱导的大鼠精神分裂症模型非常适合于这一目的，因为在腹侧海马区(VH)诱导局灶性损伤的关键时期与最容易受到AED诱导的神经元凋亡的发育期相同。我们的一般工作假设是，在出生后第二周促进大鼠神经元凋亡的AEDs将在以后的生活中增强损伤诱导的行为和认知障碍。同时，我们预测，我们最近发现在幼年大鼠身上缺乏促进细胞死亡作用的AEDs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损害的不良行为结果。通过研究VH损害和AED暴露之间的相互作用，以及VH损害和癫痫发作经历之间的相互作用，我们将确定这些潜在风险因素中的一个或两个是否增加了不良精神结果的可能性，这反映在一系列评估活动、社交互动、学习和记忆以及对多巴胺兴奋剂挑战的反应的测试中。这些信息将为未来对导致癫痫障碍和精神分裂症共病的因素(S)的长期研究奠定坚实的基础。为实现拟议的具体目标，将在一方面具有癫痫专业知识的调查人员和另一方面具有精神疾病专业知识的研究人员之间建立独特的机构间合作。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，癫痫和癫痫发作会增加包括精神分裂症在内的一些精神疾病的易感性。由于癫痫发作是用抗癫痫药物(AED)治疗的，因此AED治疗很有可能成为这种易感性的一个促成因素。在这项拟议的研究中，我们将研究在精神分裂症的神经发育动物模型中，抗精神病药物和/或反复癫痫暴露是否会增加精神病的易感性。这项研究还旨在确定不会使患有癫痫的新生儿和孕妇患上精神分裂样障碍的抗癫痫药物。

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.