SCN1A dysfunction and neuropsychiatric comorbidities

描述（由申请人提供）：SCN1A电压门控钠通道（VGSC）突变导致越来越多的疾病，包括Dravet综合征（DS）和遗传性癫痫伴热性癫痫发作（GEFS+）。退行性痴呆是一种灾难性的早期生命脑病，与长期和反复发作的早期生命发热性癫痫（FSs）、难治性无热性癫痫、共济失调和智力残疾有关。GEFS+是一种遗传性疾病，其特征是持续超过6岁的fs，并发展为多种成人癫痫亚型。迄今为止，研究主要集中在这些疾病的发作部分；然而，我们现在认识到癫痫发作通常伴随着认知停滞/下降、多动和一些行为合并症的发展，包括自闭症和精神病特征。虽然癫痫发作频率在成年期确实有下降的趋势，但这些合并症仍然存在，是这一患者群体临床管理的主要挑战。目前，与SCN1A功能障碍相关的认知和行为结果尚不清楚，影响这些缺陷严重程度的因素尚不清楚。减轻这些合并症对生活质量的影响

DESCRIPTION (provided by applicant): Mutations in the SCN1A voltage-gated sodium channel (VGSC) are responsible for a growing number of disorders, including Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+). DS is a catastrophic early-life encephalopathy associated with prolonged and recurrent early-life febrile seizures (FSs), treatment-resistant afebrile epilepsy, ataxia, and intellectual disability. GEFS+ is an inherited disorder characterized by FSs that persist beyond the age of six and the development of a wide range of adult epilepsy subtypes. To date, research has focused mainly on the seizure component of these disorders; however, we now recognize that seizure onset is often followed by cognitive stagnation/decline, hyperactivity, and the development of a number of behavioral comorbidities, including autistic and psychotic traits. Although seizure frequency does tend to decline during adulthood, these comorbidities persist and are a major challenge in the clinical management of this patient population. Currently, the cognitive and behavioral outcomes associated with SCN1A dysfunction are poorly characterized, and the factors that influence the severity of these deficits unknown. Mitigating the impact of these comorbidities on quality-of-life outcomes will require broader research efforts to better characterize these cognitive and behavioral deficits, as well as identify factors that influence their severity. Towards this end, te proposed experiments in this R21 application will use Scn1a mouse models developed in our laboratory to address several fundamental gaps in our knowledge. Specifically, we will 1) better define the cognitive and behavioral deficits that result from altered SCN1A function, 2) determine whether prolonged early-life FSs, which are a common clinical feature of SCN1A-derived epilepsies, are likely to contribute to the worsening of cognitive and behavioral outcomes, and 3) determine whether the emergence of cognitive and behavioral abnormalities requires altered SCN1A function during the early period of postnatal brain development or is an invariant (age-independent) outcome of altered SCN1A function. These experiments are both innovative and clinically relevant, and will stimulate much-needed translational research.