Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo 187-8502, Japan; Department of NCNP Brain Physiology and Pathology, Graduate school of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo, Tokyo 113-8510 Japan; Department of Neurology, Kansai Medical University, Osaka 573-1010, Japan.
Department of Degenerative Neurological Diseases, National Institute of Neuroscience, NCNP, Kodaira, Tokyo 187-8502, Japan; Department of Neuropsychopharmacology, National Institute of Mental Health, NCNP, Kodaira, Tokyo 187-8502, Japan.
Prog Neurobiol. 2022 Sep;216:102288. doi: 10.1016/j.pneurobio.2022.102288. Epub 2022 May 30.
Duchenne muscular dystrophy (DMD) is a muscle disorder caused by DMD mutations and is characterized by neurobehavioural comorbidities due to dystrophin deficiency in the brain. The lack of Dp140, a dystrophin short isoform, is clinically associated with intellectual disability and autism spectrum disorders (ASDs), but its postnatal functional role is not well understood. To investigate synaptic function in the presence or absence of brain Dp140, we utilized two DMD mouse models, mdx23 and mdx52 mice, in which Dp140 is preserved or lacking, respectively. ASD-like behaviours were observed in pups and 8-week-old mdx52 mice lacking Dp140. Paired-pulse ratio of excitatory postsynaptic currents, glutamatergic vesicle number in basolateral amygdala neurons, and glutamatergic transmission in medial prefrontal cortex-basolateral amygdala projections were significantly reduced in mdx52 mice compared to those in wild-type and mdx23 mice. ASD-like behaviour and electrophysiological findings in mdx52 mice were ameliorated by restoration of Dp140 following intra-cerebroventricular injection of antisense oligonucleotide drug-induced exon 53 skipping or intra-basolateral amygdala administration of Dp140 mRNA-based drug. Our results implicate Dp140 in ASD-like behaviour via altered glutamatergic transmission in the basolateral amygdala of mdx52 mice.
杜氏肌营养不良症（DMD）是一种肌肉疾病，由 DMD 突变引起，其特征是由于大脑中缺乏肌营养不良蛋白而导致神经行为合并症。Dp140 是一种肌营养不良蛋白的短亚型，如果缺乏，与智力障碍和自闭症谱系障碍（ASD）相关，但它在出生后的功能作用尚不清楚。为了研究存在或不存在脑 Dp140 时的突触功能，我们利用了两种 DMD 小鼠模型，mdx23 和 mdx52 小鼠，分别保留和缺乏 Dp140。在缺乏 Dp140 的 mdx52 小鼠幼崽和 8 周龄的小鼠中观察到 ASD 样行为。与野生型和 mdx23 小鼠相比，mdx52 小鼠的兴奋性突触后电流的成对脉冲比、基底外侧杏仁核神经元中的谷氨酸能囊泡数量以及内侧前额叶皮层-基底外侧杏仁核投射中的谷氨酸能传递均显著降低。在 mdx52 小鼠中，通过鞘内注射反义寡核苷酸药物诱导的外显子 53 跳跃或向基底外侧杏仁核内给予 Dp140 mRNA 药物来恢复 Dp140，可改善 ASD 样行为和电生理发现。我们的研究结果表明，Dp140 通过改变 mdx52 小鼠基底外侧杏仁核中的谷氨酸能传递，参与了 ASD 样行为。
