Impairment of cortical GABAergic synaptic transmission in an environmental rat model of autism.
Impairment of cortical GABAergic synaptic transmission in an environmental rat model of autism.
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DOI：
10.1017/s1461145712001216
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发表时间：
2013-07
期刊：
影响因子：
--
通讯作者：
Atzori M
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文献类型：
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作者：
Banerjee A;García-Oscos F;Roychowdhury S;Galindo LC;Hall S;Kilgard MP;Atzori M
自闭症谱系障碍（ASD）的生物学机制在很大程度上是未知的，尽管广泛的研究。ASD的特征在于包括颞叶皮质在内的多个脑区的功能改变以及突触兴奋：抑制比增加。虽然许多研究都在寻找ASD兴奋增加的证据，但很少有人研究抑制减少的可能性。我们通过用膜片钳监测抑制性突触后电流（IPSC）来表征ASD模型[产前注射丙戊酸（VPA）的母亲的后代]大鼠颞叶皮层中的皮层γ-氨基丁酸（GABA）能系统。我们发现，与对照组相比，VPA动物的许多抑制特征发生了严重改变。其中包括微型IPSC的频率，电诱发IPSC的上升时间和衰减时间，其输入/输出曲线的斜率和饱和度，以及肾上腺素能和毒蕈碱激动剂和突触GABAA受体变构调节剂唑吡坦（但不是突触外调节剂加波沙朵）对它们的调节。我们的数据表明，无论是前和突触后，但不是突触外，抑制传输受损的VPA注射母亲的后代。我们推测，GABA能系统的损伤对突触兴奋和抑制之间的比率增加有重要作用，这在遗传易感个体中可能会改变负责ASD核心的情感，沟通和社交障碍的皮质回路。
The biological mechanisms of autism spectrum disorders (ASDs) are largely unknown in spite of extensive research. ASD is characterized by altered function of multiple brain areas including the temporal cortex and by an increased synaptic excitation:inhibition ratio. While numerous studies searched for evidence of increased excitation in ASD, fewer have investigated the possibility of reduced inhibition. We characterized the cortical γ-amino butyric acid (GABA)ergic system in the rat temporal cortex of an ASD model [offspring of mothers prenatally injected with valproic acid (VPA)], by monitoring inhibitory post-synaptic currents (IPSCs) with patch-clamp. We found that numerous features of inhibition were severely altered in VPA animals compared to controls. Among them were the frequency of miniature IPSCs, the rise time and decay time of electrically-evoked IPSCs, the slope and saturation of their input/output curves, as well as their modulation by adrenergic and muscarinic agonists and by the synaptic GABAA receptor allosteric modulator zolpidem (but not by the extra-synaptic modulator gaboxadol). Our data suggest that both pre- and post-synaptic, but not extra-synaptic, inhibitory transmission is impaired in the offspring of VPA-injected mothers. We speculate that impairment in the GABAergic system critically contributes to an increase in the ratio between synaptic excitation and inhibition, which in genetically predisposed individuals may alter cortical circuits responsible for emotional, communication and social impairments at the core of ASD.