Neuroscience Institute, National Research Council (CNR) Pisa, Italy ; Laboratory of Neurobiology, Scuola Normale Superiore Pisa, Italy.
Laboratory of Molecular Neuropathology, Centre for Integrative Biology, University of Trento Mattarello, Trento, Italy.
Front Cell Neurosci. 2014 Jun 17;8:163. doi: 10.3389/fncel.2014.00163. eCollection 2014.
The maturation of the GABAergic system is a crucial determinant of cortical development during early postnatal life, when sensory circuits undergo a process of activity-dependent refinement. An altered excitatory/inhibitory balance has been proposed as a possible pathogenic mechanism of autism spectrum disorders (ASD). The homeobox-containing transcription factor Engrailed-2 (En2) has been associated to ASD, and En2 knockout (En2 (-/-)) mice show ASD-like features accompanied by a partial loss of cortical GABAergic interneurons. Here we studied GABAergic markers and cortical function in En2 (-/-) mice, by exploiting the well-known anatomical and functional features of the mouse visual system. En2 is expressed in the visual cortex at postnatal day 30 and during adulthood. When compared to age-matched En2 (+/+) controls, En2 (-/-) mice showed an increased number of parvalbumin (PV(+)), somatostatin (SOM(+)), and neuropeptide Y (NPY(+)) positive interneurons in the visual cortex at P30, and a decreased number of SOM(+) and NPY(+) interneurons in the adult. At both ages, the differences in distinct interneuron populations observed between En2 (+/+) and En2 (-/-) mice were layer-specific. Adult En2 (-/-) mice displayed a normal eye-specific segregation in the retino-geniculate pathway, and in vivo electrophysiological recordings showed a normal development of basic functional properties (acuity, response latency, receptive field size) of the En2 (-/-) primary visual cortex. However, a significant increase of binocularity was found in P30 and adult En2 (-/-) mice, as compared to age-matched controls. Differently from what observed in En2 (+/+) mice, the En2 (-/-) primary visual cortex did not respond to a brief monocular deprivation performed between P26 and P29, during the so-called "critical period." These data suggest that altered GABAergic circuits impact baseline binocularity and plasticity in En2 (-/-) mice, while leaving other visual functional properties unaffected.
GABA 能系统的成熟是出生后早期皮质发育的关键决定因素，在此期间，感觉回路经历了一个依赖活动的精细化过程。兴奋性/抑制性平衡的改变被认为是自闭症谱系障碍 (ASD) 的一种可能的致病机制。含有同源盒的转录因子 Engrailed-2 (En2) 与 ASD 有关，En2 敲除 (En2 (-/-)) 小鼠表现出 ASD 样特征，同时皮质 GABA 能中间神经元部分丢失。在这里，我们利用小鼠视觉系统众所周知的解剖学和功能特征，研究了 En2 (-/-) 小鼠的 GABA 能标记物和皮质功能。En2 在出生后 30 天和成年期在视皮层中表达。与年龄匹配的 En2 (+/+) 对照组相比，En2 (-/-) 小鼠在 P30 时视皮层中 PV(+)、SOM(+) 和 NPY(+) 阳性中间神经元数量增加，而成年时 SOM(+) 和 NPY(+) 阳性中间神经元数量减少。在这两个年龄阶段，En2 (+/+) 和 En2 (-/-) 小鼠之间观察到的不同中间神经元群体的差异具有层特异性。成年 En2 (-/-) 小鼠在视网膜-视交叉通路中表现出正常的眼特异性分离，体内电生理记录显示 En2 (-/-) 初级视皮层的基本功能特性 (敏锐度、反应潜伏期、感受野大小) 正常发育。然而，与年龄匹配的对照组相比，P30 和成年 En2 (-/-) 小鼠的双眼性显著增加。与在 En2 (+/+) 小鼠中观察到的情况不同，En2 (-/-) 初级视皮层在 P26 至 P29 之间进行的短暂单眼剥夺期间没有反应，此时称为“关键期”。这些数据表明，改变的 GABA 能回路会影响 En2 (-/-) 小鼠的基线双眼性和可塑性，而不影响其他视觉功能特性。
