The use of antiepileptic drugs (AEDs) in pregnancy and early infancy poses special challenges and concerns, as even transient exposure to certain drugs during CNS development may impede subsequent neuronal and synaptic development. Several AEDs, including phenobarbital and phenytoin, when given in therapeutically relevant doses to rats during the early postnatal period, cause a pronounced increase in apoptotic cell death in several brain regions. Other drugs such as lamotrigine (in low or moderate doses) and levetiracetam are devoid of this effect. We have recently discovered a single exposure to phenobarbital, at the time of peak vulnerability to the propapoptotic action (postnatal day 7 in the rat), resulted In the suppression of the normal, developmental increase in the frequency of inhibitory post-synaptic currents (IPSCs) recorded via patch clamp from striatal medium spiny neurons (MSNs) in slices taken between postnatal day 10 and 14. We have also identified impairments in adult rotorod performance in rats treated at P7 with a proapoptotic dose of phenytoin, a reduction in prepulse inhibition (a measure of sensory-motor gating) and a reduction in seizure threshold to pentylenetetrazol In animals treated in the first postnatal week with phenobarbital. Each of these behavioral assays are sensitive to damage or altered function in the striatum. The proposed experiments will follow up on these exciting preliminary findings to determine if there is a consistent and predictive (potentially causative) relationship between AED-induced neuronal apoptosis and impaired maturation of I PSC frequency in the striatum and/or adult behavioral toxicitiy. This will be assessed by comparing AED treatments that are proapoptotic with those that avoid this toxicity. We hypothesize that AEDs that do not cause cell death will not cause impaired maturation of IPSC frequency in striatal MSNs, nor will they result in impaired rotorod performance, reduced seizure threshold, and impaired prepulse inhibition ofthe acoustic starle response. Moreover, the extent to which a neuroprotective treatment can prevent impaired maturation of IPSC frequency in striatal MSNs and/or behavior will be evaluated to test the hypothesis that neuronal death is necessary for this adverse functional outcome. The results ofthe proposed experiments will allow us to better understand the potential functional outcomes of exposure to AEDs in late gestation or early infancy, and the extent to which induction of excessive neuronal death is a valid marker of subsequent functional impairment. Furthermore, it will identify strategies to avoid deleterious functional sequelae of AED therapy during critical developmental periods. GOALS FOR KIRSCHSTEIN-NRSA FELLOWSHIP TRAINING AND CAREER I am seeking this fellowship tp support my dissertation research in Dr. Karen Gale and Dr. Stefano Vicini's laboratories, investigating the impact of neonatal anticonvulsant drug exposure. My goal for dissertation research is to develop a broad skill set of experimental techniques that will allow me to address scientific questions at the level of molecules, cells, networks and behavior. The complementary expertise of my mentors provides such exposure. A limited portion of this support is also requested to allow me to continue to teach (present lectures to graduate and undergraduate students, and continue to direct a course entitled, """"""""Diseases and Disorders of the Brain"""""""". A key goal of my training is to complete and publish a series of focused studies on outcomes following drug exposure during development. My long-term goals are predicated on the broad training I am receiving at Georgetown. Following Georgetown I will seek post-doctoral training and then I hope to develop an independent, productive research program at an academic institution where I can ask and answer questions of interest at multiple levels of function, to maintain an active Involvement in teaching and mentoring, and to contribute to scientific discourse.
