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. ? ? ?
| Forcelli, Patrick A; Janssen, Megan J; Vicini, Stefano et al. (2012) Neonatal exposure to antiepileptic drugs disrupts striatal synaptic development. Ann Neurol 72:363-72 |
| Bhardwaj, S K; Forcelli, P A; Palchik, G et al. (2012) Neonatal exposure to phenobarbital potentiates schizophrenia-like behavioral outcomes in the rat. Neuropharmacology 62:2337-45 |
| Forcelli, Patrick A; Gale, Karen; Kondratyev, Alexei (2011) Early postnatal exposure of rats to lamotrigine, but not phenytoin, reduces seizure threshold in adulthood. Epilepsia 52:e20-2 |
| Forcelli, Patrick A; Janssen, Megan J; Stamps, Lauren A et al. (2010) Therapeutic strategies to avoid long-term adverse outcomes of neonatal antiepileptic drug exposure. Epilepsia 51 Suppl 3:18-23 |
| Kim, Jinsook; Gale, Karen; Kondratyev, Alexei (2010) Effects of repeated minimal electroshock seizures on NGF, BDNF and FGF-2 protein in the rat brain during postnatal development. Int J Dev Neurosci 28:227-32 |
