Striatal Sequelae of Perinatal Anticonvulsant Drug Treatment

描述（由申请人提供）：在妊娠期和婴儿早期使用抗癫痫药物（AED）带来了特殊的挑战和问题，因为即使在CNS发育期间短暂暴露于某些药物也可能阻碍随后的神经元和突触发育。几种AED，包括苯巴比妥和苯妥英，当在出生后早期以治疗相关剂量给予大鼠时，会导致几个脑区的凋亡细胞死亡显著增加。其他药物如拉莫三嗪（低剂量或中等剂量）和左乙拉西坦没有这种作用。我们最近发现，单次暴露于苯巴比妥，在对促凋亡作用的峰值脆弱性时（大鼠出生后7天），导致抑制性突触后电流（IPSC）频率的正常发育增加受到抑制，该频率通过膜片钳记录自出生后10天至14天之间的纹状体中型多刺神经元（MSN）切片。我们还发现，在P7时给予促凋亡剂量的苯妥英钠治疗的大鼠，其成年旋转棒性能受损，前脉冲抑制（感觉-运动门控的一种测量方法）减少，以及在出生后第一周给予苯巴比妥治疗的动物，戊四氮的癫痫发作阈值降低。这些行为测定中的每一种都对纹状体中的损伤或改变的功能敏感。拟议的实验将跟进这些令人兴奋的初步研究结果，以确定是否有一个一致的和预测（潜在的因果关系）之间的关系AED诱导的神经元凋亡和受损的成熟的I PSC的频率在纹状体和/或成人行为毒性。这将通过比较促凋亡的AED治疗与避免这种毒性的AED治疗来评估。我们假设，不引起细胞死亡的AED不会导致纹状体MSNs IPSC频率成熟受损，也不会导致旋转杆性能受损、癫痫发作阈值降低和声星反应前脉冲抑制受损。此外，将评价神经保护性治疗可以防止纹状体MSN和/或行为中IPSC频率成熟受损的程度，以检验神经元死亡是这种不良功能结果所必需的假设。实验结果将使我们更好地了解妊娠晚期或婴儿早期暴露于AED的潜在功能结果，以及过度神经元死亡的诱导在多大程度上是随后功能障碍的有效标志。此外，它将确定策略，以避免在关键发育期AED治疗的有害功能后遗症。 KIRSCHSTEIN-NRSA奖学金培训和职业目标我正在寻求这个奖学金以支持我在Karen Gale博士和Stefano Vicini博士实验室的论文研究，调查新生儿抗惊厥药物暴露的影响。我的论文研究的目标是发展一套广泛的实验技术技能，使我能够在分子，细胞，网络和行为的水平上解决科学问题。我的导师们的互补专业知识提供了这样的接触。还要求提供有限的一部分支持，使我能够继续任教（为研究生和本科生讲课，并继续指导一门名为“大脑疾病和紊乱”的课程。我培训的一个关键目标是完成并发表一系列关于开发过程中药物暴露后结果的重点研究。我的长期目标是基于我在乔治敦大学接受的广泛培训。继乔治敦大学，我将寻求博士后培训，然后我希望在一个学术机构，我可以问和回答感兴趣的问题在多个层次的功能，以保持积极参与教学和指导，并有助于科学话语的独立，富有成效的研究计划。

DESCRIPTION (provided by applicant): 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.