Saito A, Taniguchi Y, Rannals M D, Merfeld E B, Ballinger M D, Koga M, Ohtani Y, Gurley D A, Sedlak T W, Cross A, Moss S J, Brandon N J, Maher B J, Kamiya A
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Tochigi, Japan.
Mol Psychiatry. 2016 Oct;21(10):1449-59. doi: 10.1038/mp.2015.203. Epub 2016 Jan 5.
Exploring drug targets based on disease-associated molecular mechanisms during development is crucial for the generation of novel prevention and treatment strategies for neurodevelopmental psychiatric conditions. We report that prefrontal cortex (PFC)-specific postnatal knockdown of DISC1 via in utero electroporation combined with an inducible knockdown expression system drives deficits in synaptic GABAA function and dendritic development in pyramidal neurons, as well as abnormalities in sensorimotor gating, albeit without profound memory deficits. We show for the first time that DISC1 is specifically involved in regulating cell surface expression of α2 subunit-containing GABAA receptors in immature developing neurons, but not after full maturation. Notably, pharmacological intervention with α2/3 subtype-selective GABAA receptor positive allosteric modulators during the early postnatal period ameliorates dendritic deficits and behavioral abnormalities induced by knockdown of DISC1. These findings highlight a critical role of DISC1-mediated disruption of postnatal GABA signaling in aberrant PFC maturation and function.
在神经发育性精神疾病的发展过程中，基于疾病相关分子机制探索药物靶点对于制定新的预防和治疗策略至关重要。我们报告称，通过子宫内电穿孔结合诱导性敲低表达系统，在出生后对前额叶皮质（PFC）特异性敲低DISC1，会导致锥体神经元突触GABAA功能和树突发育缺陷，以及感觉运动门控异常，尽管没有严重的记忆缺陷。我们首次表明，DISC1在未成熟发育神经元中特异性参与调节含α2亚基的GABAA受体的细胞表面表达，但在完全成熟后则不然。值得注意的是，在出生后早期用α2/3亚型选择性GABAA受体正性变构调节剂进行药物干预，可改善由DISC1敲低诱导的树突缺陷和行为异常。这些发现突出了DISC1介导的出生后GABA信号破坏在PFC异常成熟和功能中的关键作用。
