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: 7313187
• 负责人: ALEXEI D KONDRATYEV
• 金额: $ 17.55万
• 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 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7313187
• 关键词: Affect; Animal Model; Animals; Antiepileptic Agents; Apoptosis; Apoptotic; Behavioral; Brain; Brain region; Carbamazepine; Cell Death; Cessation of life; Collaborations; Comorbidity; Depth; Development; Disease; Dopamine; Drug Exposure; Epidemiologic Studies; Epilepsy; Evaluation; Excitotoxic lesion; Exposure to; Factor Analysis; Febrile Convulsions; Fever; Foundations; Future; Goals; Hand; Hippocampus (Brain); Impact Seizures; Impaired cognition; Infant; Learning; Lesion; Levetiracetam; Life; Longitudinal Studies; Memory; Mental disorders; Modeling; Neonatal; Neurodevelopmental Impairment; Neurons; Newborn Animals; Numbers; Outcome; Pattern; Performance; Pharmaceutical Preparations; Pharmacotherapy; Phenobarbital; Phenytoin; Predisposition; Pregnant Women; Premature Infant; Probability; Psychotic Disorders; Public Health; Purpose; Rattus; Recording of previous events; Recurrence; Reporting; Research Personnel; Risk; Risk Factors; Schizophrenia; Seizures; Severities; Social Interaction; Solid; Staging; Synapses; Testing; Time; Week; Work; behavior test; critical developmental period; day; experience; forging; neonate; neuron apoptosis; neuron loss; postnatal; pup; research study; transcription factor

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研究精神分裂症神经发育动物模型中尚未探索的癫痫发作障碍与精神疾病之间的相互关系。无论是新生儿癫痫或癫痫发作，还是早产儿癫痫发作，是否会增加后续精神疾病的易感性一直存在一些争议。最近的流行病学研究表明，发热性发作或癫痫史与精神分裂症风险显著增加有关。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，可能会对精神预后产生不利影响，特别是在脑成熟期间给予治疗时。在出生后早期大脑发育期间使用某些aed治疗会引发几个大脑区域的凋亡神经元细胞死亡，这提高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。最近研究的精神分裂症大鼠神经发育损伤诱导模型非常适合这一目的，因为诱导腹侧海马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时期相同。我们的一般工作假设是，aed在大鼠出生后第二周促进细胞凋亡的神经元死亡，将在以后的生活中增加病变引起的行为和认知障碍。同时，我们预测，我们最近确定的在幼鼠中缺乏细胞死亡促进作用的aed不会加剧病变的影响。此外，我们还将确定诱导复发癫痫发作是否会影响新生儿Vh病变的不良行为结局。通过检查Vh病变与AED暴露之间的相互作用，以及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风险因素中是否有一个或两个增加了不良精神结局的可能性，这反映在一系列评估活动、社会互动、学习和记忆以及对多巴胺刺激物挑战的反应性的测试中。这一信息将为今后长期研究癫痫和精神分裂症共病的相关因素奠定坚实的基础。将建立一种独特的机构间合作，一方面是具有癫痫专长的研究人员，另一方面是具有精神疾病专长的研究人员，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阶段或早产儿的癫痫和发作会增加患包括精神分裂症在内的许多精神疾病的易感性。由于癫痫发作是用抗癫痫药物（AED）治疗的，因此AED治疗很有可能是导致这种易感性的一个因素。在这项研究中，我们将研究在精神分裂症的神经发育动物模型中，aed和/或反复发作暴露是否会增加精神病的易感性。这项研究的目的还在于确定抗癫痫药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。