Abstract

Introduction

Neuronal gap-junctions are extensively expressed in mammalian forebrain and suggested to contribute to state-regulation and thalamocortical network activity. However, the physiological role of gap-junctions on these processes remains poorly understood. Connexin-36 (Cxn36) is highly expressed in the brain, representing a mechanism for electrical coupling of inhibitory neurons. We examined the effects of global Cnx36 deletion on sleep/wake and spontaneous and evoked EEG activity.

Methods

We recorded in vivo EEG/EMG in Cxn36KO mice and littermate controls. Electrodes were stereotaxically implanted above frontal cortices. We analyzed sleep/wake states and algorithmically detected sleep spindles over 24 hours. Mice underwent auditory stimulation paradigms including the auditory steady state response (ASSR; 1 second train 20-50Hz clicks, 100 reps., 85dB) and mismatch negativity (MMN; 2.5kHz standard 90%, 10kHz deviant 10%, 300ms ISI, 90dB). Social behavior and investigation-evoked EEG activity were also assessed via the social habituation task (repeated 5 min exposures to novel mouse).

Results

Cnx36KO mice exhibited limited sleep/wake abnormalities (n=7/group). Power spectra of EEG revealed significant impairments in spontaneous gamma-band activity (30-80Hz; All States, Light & Dark Phases), and beta activity (15-25Hz; All States, Light Phase). Sigma activity (10-15Hz) was significantly decreased (NREM and REM, Light phase). This was particularly pronounced during NREM-REM transitions. Despite no changes in spindle density, both spindle amplitude and duration were significantly decreased in Cnx36KOs. Cxn36KOs exhibited a blunted gamma-band response to acute ketamine (15mg/kg; IP), impaired 30 & 40Hz ASSR, and an abnormal response in the MMN task (decrease ERP peak amplitude & gamma). Finally, Cxn36KO mice exhibit impaired social habituation and significantly decreased investigation evoked slow gamma-band activity (30 - 55Hz).

Conclusion

Our data suggest Cxn36 plays a critical role in regulating thalamocortical network activity. Further, impairments in Cnx36KO mice reflect abnormalities in neuropsychiatric disorders, including schizophrenia, implicating Cnx36 containing gap junctions as a novel therapeutic target.

Support

Research supported by VA CDA Award BX002130 (JMM), VA Merit Awards BX004500 (JMM), BX001404 (RB), and NIMH RO1 MH39683 (Ritchie E. Brown).

中文翻译：

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0158连接蛋白36的丧失导致与神经精神疾病有关的丘脑皮层网络活动异常

摘要

介绍

神经元间隙连接在哺乳动物的前脑中广泛表达，并提示其有助于状态调节和丘脑皮质网络活动。但是，间隙连接在这些过程中的生理作用仍然知之甚少。连接蛋白36（Cxn36）在脑中高表达，代表抑制性神经元电耦合的机制。我们检查了整体Cnx36缺失对睡眠/苏醒以及自发和诱发的EEG活动的影响。

方法

我们在Cxn36KO小鼠和同窝出生的对照组中记录了体内EEG / EMG。将电极立体定向植入额皮质上方。我们分析了睡眠/唤醒状态，并通过算法检测了24小时内的睡眠纺锤。小鼠经历了听觉刺激范例，包括听觉稳态响应（ASSR； 1秒训练20-50Hz点击次数，100次重复，85dB）和失配负性（MMN； 2.5kHz标准90％，10kHz偏离10％，300ms ISI，90dB） 。还通过社交习惯任务（重复接触新小鼠5分钟）评估了社交行为和调查诱发的EEG活动。

结果

Cnx36KO小鼠表现出有限的睡眠/苏醒异常（n = 7 /组）。脑电图的功率谱显示自发的伽玛带活动（30-80Hz；所有状态，亮相和暗相）和β活度（15-25Hz；所有状态，光相）有明显的损害。Sigma活动（10-15Hz）显着降低（NREM和REM，光相）。这在NREM-REM过渡期间特别明显。尽管主轴密度没有变化，但Cnx36KOs的主轴振幅和持续时间均显着降低。Cxn36KOs表现出对急性氯胺酮（15mg / kg; IP）的钝化伽马带反应，受损的30和40Hz ASSR，以及MMN任务中的异常反应（ERP峰值振幅和伽马降低）。最后，Cxn36KO小鼠表现出受损的社会习性，并且显着降低的研究诱发了缓慢的伽马波段活动（30-55Hz）。

结论

我们的数据表明Cxn36在调节丘脑皮层网络活动中起关键作用。此外，Cnx36KO小鼠的损伤反映出神经精神疾病（包括精神分裂症）的异常，这提示含有间隙连接的Cnx36作为新的治疗靶标。

支持

这项研究得到了VA CDA奖BX002130（JMM），VA优异奖BX004500（JMM），BX001404（RB）和NIMH RO1 MH39683（Ritchie E. Brown）的支持。