Alterations in sociability and functional brain connectivity caused by early-life seizures are prevented by bumetanide.
Alterations in sociability and functional brain connectivity caused by early-life seizures are prevented by bumetanide.
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DOI：
10.1016/j.nbd.2015.02.015
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发表时间：
2015-05
影响因子：
6.1
通讯作者：
Barry J
中科院分区：
文献类型：
--
作者：
Holmes GL;Tian C;Hernan AE;Flynn S;Camp D;Barry J
婴儿癫痫和广泛的认知和行为缺陷之间存在着很好的联系，包括自闭症谱系障碍的高发病率。尽管生命早期癫痫发作和自闭症发展之间的关系很强，但其发生的病理生理机制尚未探索。由于越来越多的证据表明自闭症是一种大脑连接障碍，我们假设早期癫痫发作会在大脑成熟过程中中断正常的大脑连接，并导致自闭症表型。正常大鼠幼鼠出生后（P）5-14天反复氟乙烯诱导的癫痫发作，然后测试，沿着控制，从P18-25发育脑振荡活动的发育变化。具体来说，我们希望了解大脑区域内和区域间的正常节律性变化如何随年龄变化，以及这种节律性是否会因早期癫痫发作而改变或中断。在大鼠幼鼠与早期生活癫痫发作，从背侧和腹侧海马和前额叶皮层的现场录音表现出显着增加的连贯性，以及在所有带宽的电压相关性下降相比，控制，而总功率和相对功率谱密度的差异很小。早期癫痫发作的大鼠在社交能力和社会新奇性测试中表现出损害，但在开放领域测量时没有表现出活动增加或广泛性焦虑的证据。此外，与早期生活癫痫发作的大鼠有较低的癫痫发作阈值比对照组，表明长期的兴奋/抑制平衡的改变。布美他尼是一种阻断NKCC 1活性并诱导EC 1向更超极化值显著转变的药理学药物，在癫痫发作时给药排除了随后的相干性和电压相关性异常，并导致正常的社交性和癫痫发作阈值。综合这些发现表明，早期癫痫发作改变了振荡的发展，并导致类似自闭症的行为。这些大脑区域之间的交流改变可能反映了自闭症谱系障碍中社会认知缺陷的生理基础。
There is a well-described association between infantile epilepsy and pervasive cognitive and behavioral deficits, including a high incidence of autism spectrum disorders. Despite the robustness of the relationship between early-life seizures and the development of autism, the pathophysiological mechanism by which this occurs has not been explored. As a result of increasing evidence that autism is a disorder of brain connectivity we hypothesized that early-life seizures would interrupt normal brain connectivity during brain maturation and result in an autistic phenotype. Normal rat pups underwent recurrent flurothyl-induced seizures from postnatal (P) day 5-14 and then tested, along with controls, for developmental alterations of development brain oscillatory activity from P18-25. Specifically we wished to understand how normal changes in rhythmicity in and between brain regions change as a function of age and if this rhythmicity is altered or interrupted by early life seizures. In rat pups with early-life seizures, field recordings from dorsal and ventral hippocampus and prefrontal cortex demonstrated marked increase in coherence as well as a decrease in voltage correlation at all bandwidths compared to controls while there were minimal differences in total power and relative power spectral densities. Rats with early-life seizures had resulting impairment in the sociability and social novelty tests but demonstrated no evidence of increased activity or generalized anxiety as measured in the open field. In addition, rats with early-life seizures had lower seizure thresholds than controls, indicating long-standing alterations in the excitatory/inhibition balance. Bumetanide, a pharmacological agent that blocks the activity of NKCC1 and induces a significant shift of ECl toward more hyperpolarized values, administration at the time of the seizures precluded the subsequent abnormalities in coherence and voltage correlation and resulted in normal sociability and seizure threshold. Taken together these findings indicate that early-life seizures alter the development of oscillations and result in autistic-like behaviors. The altered communication between these brain regions could reflect the physiological underpinnings underlying social cognitive deficits seen in autism spectrum disorders.