Astrocyte-Mediated Hepatocyte Growth Factor/Scatter Factor Supplementation Restores GABAergic Interneurons and Corrects Reversal Learning Deficits in Mice
Astrocyte-Mediated Hepatocyte Growth Factor/Scatter Factor Supplementation Restores GABAergic Interneurons and Corrects Reversal Learning Deficits in Mice
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DOI：
10.1523/jneurosci.5268-09.2010
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发表时间：
2010-02-24
影响因子：
5.3
通讯作者：
Powell, Elizabeth M.
中科院分区：
文献类型：
--
作者：
Bissonette, Gregory B.;Bae, Mihyun H.;Powell, Elizabeth M.
许多精神和神经系统疾病在多个大脑区域呈现持续的神经解剖学异常，这可能反映了发育障碍的共同起源。在哺乳动物中，许多局部 GABA 能抑制性中间神经元来自单一皮质下来源。成人中 GABA 能中间神经元个体发育的扰动可能通过额叶大脑皮层和纹状体区域的中间神经元缺陷反映出来。据报道，精神分裂症和额叶癫痫患者的 GABA 能回路遭到破坏，可能导致其行为灵活性受损。本研究表明，一种行为灵活性，即逆转学习，依赖于适当数量的 GABA 能中间神经元。中间神经元个体发育异常的小鼠在眶额皮质和纹状体区域表达小清蛋白的 GABA 能局部中间神经元数量减少，并且逆转倾向受损。使用遗传方法，通过补充外源性产后生长因子来恢复解剖学和功能缺陷。这些结果表明，GABA 能局部电路对于调节行为灵活性至关重要，并且出生缺陷可以通过补充关键的生长因子来纠正。
Many psychiatric and neurological disorders present persistent neuroanatomical abnormalities in multiple brain regions that may reflect a common origin for a developmental disturbance. In mammals, many of the local GABAergic inhibitory interneurons arise from a single subcortical source. Perturbations in the ontogeny of the GABAergic interneurons may be reflected in the adult by interneuron deficits in both frontal cerebral cortical and striatal regions. Disrupted GABAergic circuitry has been reported in patients with schizophrenia and frontal lobe epilepsy and may contribute to their associated impairments in behavioral flexibility. The present study demonstrates that one type of behavioral flexibility, reversal learning, is dependent upon proper numbers of GABAergic interneurons. Mice with abnormal interneuron ontogeny have reduced numbers of parvalbumin-expressing GABAergic local interneurons in the orbitofrontal cortical and striatal regions and impaired reversal leaning. Using a genetic approach, both the anatomical and functional deficiencies are restored with exogenous postnatal growth factor supplementation. These results show that GABAergic local circuitry is critical for modulating behavioral flexibility and that birth defects can be corrected by replenishing crucial growth factors.