Striatal Sequelae of Perinatal Anticonvulsant Drug Treatment

描述（由申请人提供）：妊娠期和婴儿早期使用抗癫痫药物（aed）会带来特殊的挑战和担忧，因为在中枢神经系统发育期间，即使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。在产后早期给予大鼠治疗相关剂量的几种AEDs，包括苯巴比妥和苯妥英，可导致几个脑区凋亡细胞死亡的显著增加。其他药物如拉莫三嗪（低或中剂量）和左乙拉西坦没有这种作用。我们最近发现，在对促光作用最脆弱的时候（大鼠出生后第7天），单次暴露于苯巴比妥，会抑制正常的、发育性的抑制性突触后电流（IPSCs）频率的增加，这种频率是通过膜片钳在出生后第10天至14天之间从纹状体中棘神经元（MSNs）切片中记录的。我们还发现，在P7时使用促凋亡剂量的苯妥英治疗的大鼠的成年旋足功能受损，减少了脉冲前抑制（一种感觉-运动门控的测量），并降低了在出生后第一周使用苯巴比妥治疗的动物对戊四唑的癫痫阈值。这些行为分析对纹状体的损伤或功能改变都很敏感。拟议的实验将继续这些令人兴奋的初步发现，以确定在aed诱导的神经元凋亡与纹状体I PSC频率成熟受损和/或成人行为毒性之间是否存在一致和预测性（潜在的因果关系）。这将通过比较促凋亡和避免这种毒性的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msnn中IPSC频率的成熟受损，也不会导致旋转杆性能受损、癫痫发作阈值降低和声惊反应的脉冲前抑制受损。此外，将评估神经保护治疗在多大程度上可以防止纹状体msn中IPSC频率的成熟受损和/或行为，以验证神经元死亡是这种不良功能结果所必需的假设。拟议的实验结果将使我们更好地了解妊娠晚期或婴儿期早期暴露于aed的潜在功能结果，以及诱导过度神经元死亡的程度是随后功能损伤的有效标志。此外，它将确定在关键发育时期避免AED治疗的有害功能后遗症的策略。我正在寻求这项奖学金来支持我在Karen Gale博士和Stefano Vicini博士实验室的论文研究，研究新生儿抗惊厥药物暴露的影响。我的论文研究目标是开发一套广泛的实验技术技能，使我能够解决分子、细胞、网络和行为层面的科学问题。我的导师们互补的专业知识提供了这样的机会。我还要求提供有限的一部分支持，让我能够继续为研究生和本科生授课，并继续指导一门名为“大脑疾病和失调”的课程。我培训的一个关键目标是完成并发表一系列关于药物暴露后发展结果的重点研究。我的长期目标是建立在我在乔治敦大学接受的广泛训练之上的。从乔治敦大学毕业后，我将寻求博士后培训，然后我希望在一个学术机构开展一个独立的、富有成效的研究项目，在那里我可以在多个层面上提出和回答感兴趣的问题，保持积极参与教学和指导，并为科学论述做出贡献。

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.