Villacres Juan E, Riveira Nicholas, Kim Sohmee, Colgin Laura L, Noebels Jeffrey L, Lopez Angel Y
Center for Learning and Memory, The University of Texas at Austin, Austin, TX, 78712-0805, USA.
Department of Neuroscience, The University of Texas at Austin, Austin, TX, 78712-0805, USA.
Transl Psychiatry. 2023 Dec 20;13(1):403. doi: 10.1038/s41398-023-02700-2.
ANK3 is a leading bipolar disorder (BD) candidate gene in humans and provides a unique opportunity for studying epilepsy-BD comorbidity. Previous studies showed that deletion of Ank3-1b, a BD-associated variant of Ank3 in mice leads to increased firing threshold and diminished action potential dynamic range of parvalbumin (PV) interneurons and absence epilepsy, thus providing a biological mechanism linking epilepsy and BD. To explore the behavioral overlap of these disorders, we characterized behavioral patterns of Ank3-1b KO mice during overnight home-cage activity and examined network activity during these behaviors using paired video and EEG recordings. Since PV interneurons contribute to the generation of high-frequency gamma oscillations, we anticipated changes in the power of neocortical EEG signals in the gamma frequency range (> 25 Hz) during behavioral states related to human BD symptoms, including abnormal sleep, hyperactivity, and repetitive behaviors. Ank3-1b KO mice exhibited an overall increase in slow gamma (~25-45 Hz) power compared to controls, and slow gamma power correlated with seizure phenotype severity across behaviors. During sleep, increased slow gamma power correlated with decreased time spent in the rapid eye movement (REM) stage of sleep. Seizures were more common during REM sleep compared to non-REM (NREM) sleep. We also found that Ank3-1b KO mice were hyperactive and exhibited a repetitive behavior phenotype that co-occurred with increased slow gamma power. Our results identify a novel EEG biomarker associating Ank3 genetic variation with BD and epilepsy and suggest modulation of gamma oscillations as a potential therapeutic target.
ANK3是人类双相情感障碍（BD）的主要候选基因，为研究癫痫与BD的共病提供了独特的机会。先前的研究表明，小鼠中Ank3的BD相关变体Ank3-1b缺失会导致小白蛋白（PV）中间神经元的放电阈值升高和动作电位动态范围减小，以及失神癫痫，从而提供了一种将癫痫与BD联系起来的生物学机制。为了探索这些疾病的行为重叠，我们对Ank3-1b基因敲除小鼠在夜间笼内活动期间的行为模式进行了表征，并使用配对视频和脑电图记录检查了这些行为期间的网络活动。由于PV中间神经元有助于高频伽马振荡的产生，我们预计在与人类BD症状相关的行为状态（包括异常睡眠、多动和重复行为）期间，新皮质脑电图信号在伽马频率范围（>25Hz）的功率会发生变化。与对照组相比，Ank3-1b基因敲除小鼠的慢伽马（~25-45Hz）功率总体增加，并且慢伽马功率与各行为的癫痫发作表型严重程度相关。在睡眠期间，慢伽马功率增加与快速眼动（REM）睡眠阶段所花时间减少相关。与非快速眼动（NREM）睡眠相比，REM睡眠期间癫痫发作更为常见。我们还发现，Ank3-1b基因敲除小鼠多动，并表现出与慢伽马功率增加同时出现的说重复行为表型。我们的结果确定了一种将Ank3基因变异与BD和癫痫相关联的新型脑电图生物标志物，并表明调节伽马振荡是一个潜在的治疗靶点。
