Loss of GABAergic neurons in the hippocampus and cerebral cortex of Engrailed-2 null mutant mice: Implications for autism spectrum disorders

被引:82
作者
Sgado, Paola [1 ]
Genovesi, Sacha [1 ]
Kalinovsky, Anna [2 ]
Zunino, Giulia [1 ]
Macchi, Francesca [3 ]
Allegra, Manuela [3 ]
Murenu, Elisa [4 ]
Provenzano, Giovanni [1 ]
Tripathi, Prem Prakash [3 ]
Casarosa, Simona [3 ,4 ]
Joyner, Alexandra L. [2 ]
Bozzi, Yuri [1 ,3 ]
机构
[1] Univ Trent, Ctr Integrat Biol CIBIO, Lab Mol Neuropathol, I-38123 Trento, Italy
[2] Sloan Kettering Inst, Dev Biol Program, New York, NY USA
[3] CNR Neurosci Inst, Pisa, Italy
[4] Univ Trent, Ctr Integrat Biol CIBIO, Dev Neurobiol Lab, I-38123 Trento, Italy
基金
美国国家卫生研究院;
关键词
Homeobox transcription factor; Inhibition; Interneuron; Parvalbumin; Neurodevelopmental disorder; MESENCEPHALIC DOPAMINERGIC-NEURONS; HOMEOBOX-TRANSCRIPTION-FACTOR; CEREBELLAR DEVELOPMENT; KNOCKOUT MICE; GLUTAMATE-DECARBOXYLASE; INDUCED SEIZURES; PURKINJE-CELLS; MOUSE MODELS; GENES; EXPRESSION;
D O I
10.1016/j.expneurol.2013.01.021
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The homeobox-containing transcription factor Engrailed-2 (En2) is involved in patterning and neuronal differentiation of the midbrain/hindbrain region, where it is prominently expressed. En2 mRNA is also expressed in the adult mouse hippocampus and cerebral cortex, indicating that it might also function in these brain areas. Genome-wide association studies revealed that En2 is a candidate gene for autism spectrum disorders (ASD), and mice devoid of its expression (En2(-/-) mice) display anatomical, behavioral and clinical "autistic-like" features. Since reduced GABAergic inhibition has been proposed as a possible pathogenic mechanism of ASD, we hypothesized that the phenotype of En2(-/-) mice might include defective GABAergic innervation in the forebrain. Here we show that the Engrailed proteins are present in postnatal GABAergic neurons of the mouse hippocampus and cerebral cortex, and adult En2(-/-) mice show reduced expression of GABAergic marker mRNAs in these areas. In addition, reduction in parvalbumin (PV), somatostatin (SOM) and neuropeptide Y (NPY) expressing interneurons is detected in the hippocampus and cerebral cortex of adult En2(-/-) mice. Our results raise the possibility of a link between altered function of En2, anatomical deficits of GABAergic forebrain neurons and the pathogenesis of ASD. (C) 2013 Elsevier Inc. All rights reserved.
引用
收藏
页码:496 / 505
页数:10
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