Absence epilepsy is characterized by a distinct spike-and-wave discharge (SWD) in the electroencephalogram (EEG). Unlike the typical form of absence epilepsy, atypical absence epilepsy (AAE) showing slow SWD (<3 Hz) is characterized by severely abnormal cognition and neurodevelopmental or neurological outcomes in humans. Plus, only thalamocortical circuitry is involved in the typical form of absence epilepsy, whereas AAE is known to involve limbic circuitry including hippocampus as well as thalamocortical circuitry. However, despite the severe cognitive and neurodevelopmental outcomes in AAE, the relationship between AAE and social-behavioral dysfunctions has not been defined well, either experimentally or in patients with AAE.
In this study, we characterized social behaviors in the mouse model of AAE.AAE in the mouse was induced by repeated postnatal administration of AY-9944 (AY), a cholesterol biosynthesis inhibitor, every 6 days from postnatal day (P) 2 to P20. SWD was investigated in frontal cortex, parietal cortex, and hippocampus by long-term video-EEG monitoring. AY-treated mice performed various social behavior tests such as sociability/social novelty preference, social interaction with a juvenile conspecific, observational fear, and resident-intruder aggression. As a result, AY-treated mice exhibited spontaneous, recurrent, and synchronous SWD. The average frequency of SWD was 4-5 Hz in EEG recordings. Furthermore, AY-treated mice showed behavioral dysfunction in social interactions with a juvenile conspecific, sociability/social novelty preference, and social fear learning tests. AY-treated mice also exhibited increased levels of offensive behaviors in a resident-intruder test.
Together, these results suggest abnormal epileptic activity during postnatal development and severely altered social behaviors in AY-9944 model, which may help to reveal neural mechanisms underlying AAE. This study can provide novel and valuable information about brain diseases or disorders such as Lennox-Gastaut syndrome, in which AAE is a major symptom. Thus, our findings may help to improve medical management and quality of life in patients with AAE.
결여성 뇌전증 (absence epilepsy)은 크게 정형 결여성 뇌전증 (typical absence epilepsy)과 비정형 결여성 뇌전증 (atypical absence epilepsy)으로 나뉜다. 이중 비정형 결여성 뇌전증은 인지 (cognition) 그리고 신경발달 (neurodevelopment) 상에서 심각한 이상 징후를 보이며, 약물 (drug)에 의한 치료가 어렵다. 그럼에도 불구하고 비정형 결여성 뇌전증에 대한 연구, 특히, 사회적 행동 (social behavior)에 대한 연구는 매우 미비한 실정이다.
본 연구에서는 생 후 2, 8, 14, 20 일에 AY-9944를 반복적으로 투여하여 비정형 결여성 뇌전증 생쥐 모델을 만들고, 사회성 (sociability), 사회적 새로움 선호 (social novelty preference), 사회적 상호작용 (social interaction), 관측 공포 조건화 (observational fear conditioning), 그리고 거주자-침입자 (resident-intruder) 실험 등을 통해 비정형 결여서 뇌전증 생쥐 모델의 사회적 행동 특징을 정의하였다. 비정형 결여성 뇌전증 동물 모델은 사회성, 사회적 상호작용, 관측 공포 조건화 실험 모두에서 대조군 (control)에 비해 낮은 수준을 보였으며, 사회적 새로움 선호는 보이지 않았다. 또한, 거주자-침입자 실험에서는 대조군에 비해 높은 공격 성향을 보였다.
본 실험 결과, 비정형 결여성 뇌전증 동물 모델은 사회적 행동이 심각하게 결여되어 있었다. 이러한 실험 결과는 비정형 결여성 간질 환자의 행동학적 특징과 병인학적 (pathogenesis) 관점에서의 이해에 도움이 될 것이며, 비정형 결여성 간질에 기인하는 신경 메커니즘을 밝히는 데 도움이 될 것이라 기대된다.
