Department of Anatomy & Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
J Neurosci. 2010 Feb 24;30(8):2918-23. doi: 10.1523/JNEUROSCI.5268-09.2010.
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.
许多精神和神经疾病在多个大脑区域都存在持续的神经解剖异常，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一个单一的皮质下来源。GABA 能中间神经元的发育障碍可能在成年期表现为额叶皮质和纹状体区域的中间神经元缺失。在精神分裂症和额叶癫痫患者中已经报道了 GABA 能回路的中断，并且可能导致其相关的行为灵活性受损。本研究表明，一种行为灵活性，即反转学习，取决于 GABA 能中间神经元的适当数量。具有异常中间神经元发生的小鼠在眶额皮质和纹状体区域中表达 Parvalbumin 的 GABA 能局部中间神经元数量减少，并且反转学习受损。使用遗传方法，通过外源性产后生长因子补充，恢复了解剖和功能缺陷。这些结果表明，GABA 能局部回路对于调节行为灵活性至关重要，并且可以通过补充关键生长因子来纠正出生缺陷。
