Data_Sheet_1_Hippocampal ΔFosB expression is associated with cognitive impairment in a subgroup of patients with childhood epilepsies.pdf

Epilepsy is a chronic neurological disorder characterized by recurrent seizures, and is often comorbid with other neurological and neurodegenerative diseases, such as Alzheimer's disease (AD). Patients with recurrent seizures often present with cognitive impairment. However, it is unclear how seizures, even when infrequent, produce long-lasting deficits in cognition. One mechanism may be seizure-induced expression of ΔFosB, a long-lived transcription factor that persistently regulates expression of plasticity-related genes and drives cognitive dysfunction. We previously found that, compared with cognitively-intact subjects, the activity-dependent expression of ΔFosB in the hippocampal dentate gyrus (DG) was increased in individuals with mild cognitive impairment (MCI) and in individuals with AD. In MCI patients, higher ΔFosB expression corresponded to lower Mini-Mental State Examination scores. Surgically resected DG tissue from patients with temporal lobe epilepsy also showed robust ΔFosB expression; however, it is unclear whether ΔFosB expression also corresponds to cognitive dysfunction in non-AD-related epilepsy. To test whether DG ΔFosB expression is indicative of cognitive impairment in epilepsies with different etiologies, we assessed ΔFosB expression in surgically-resected hippocampal tissue from 33 patients with childhood epilepsies who had undergone Wechsler Intelligence Scale for Children (WISC) testing prior to surgery. We found that ΔFosB expression is inversely correlated with Full-Scale Intelligence Quotient (FSIQ) in patients with mild to severe intellectual disability (FSIQ < 85). Our data indicate that ΔFosB expression corresponds to cognitive impairment in epilepsies with different etiologies, supporting the hypothesis that ΔFosB may epigenetically regulate gene expression and impair cognition across a wide range of epilepsy syndromes.

癫痫（Epilepsy）是一种以反复发作性癫痫发作为特征的慢性神经系统疾病，常与其他神经系统疾病及神经退行性疾病共病，例如阿尔茨海默病（Alzheimer's Disease, AD）。癫痫反复发作患者常伴随认知功能障碍。然而，即便发作频率较低，癫痫如何引发持续性认知功能缺陷的机制仍不明确。其中一种潜在机制可能是癫痫发作诱导ΔFosB表达升高；ΔFosB是一种长寿命转录因子，可持续调控可塑性相关基因的表达，进而介导认知功能障碍。我们既往研究发现，与认知功能完整的受试者相比，轻度认知障碍（mild cognitive impairment, MCI）患者及阿尔茨海默病患者的海马齿状回（hippocampal dentate gyrus, DG）中，活性依赖性ΔFosB表达水平升高。在轻度认知障碍患者中，ΔFosB表达水平越高，其简易精神状态检查表（Mini-Mental State Examination, MMSE）得分越低。颞叶癫痫患者手术切除的海马齿状回组织中，ΔFosB同样呈现高表达；但目前尚不清楚在非阿尔茨海默病相关性癫痫中，ΔFosB表达是否同样与认知功能障碍相关。为验证海马齿状回ΔFosB表达是否可作为不同病因癫痫患者认知功能障碍的标志物，我们对33例儿童癫痫患者手术切除的海马组织中ΔFosB表达水平进行了检测；所有受试者均在术前接受了韦氏儿童智力量表（Wechsler Intelligence Scale for Children, WISC）评估。我们发现，在轻至重度智力障碍（总智商FSIQ <85）患者中，ΔFosB表达水平与总智商（Full-Scale Intelligence Quotient, FSIQ）呈负相关。本研究数据表明，ΔFosB表达水平与不同病因癫痫患者的认知功能障碍相关，这一结果支持以下假说：ΔFosB可通过表观遗传机制调控基因表达，进而在多种癫痫综合征中引发认知功能损害。