A dystonia-like movement disorder with brain and spinal neuronal defects is caused by mutation of the mouse laminin β1 subunit, Lamb1

eLife

Laurie J Ozelius¹  Johnny Salameh²  Allison Brashear³  Elena Arystarkhova⁴  Yi Bessie Liu⁴  Kathleen J Sweadner⁴  Kamran Khodakhah⁵  Ambika Tewari⁵  Thomas G Hampton⁶ 

[1] Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States;Department of Neurology, University of Massachusetts Medical School, Worcester, United States;Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, United States;Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States;Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, United States;Neuroscience Discovery Core, Mouse Specifics Inc., Framingham, United States;

关键词: movement disorder;    exome sequencing;    spinal cord circuits;    extracellular matrix;    laminin;    synapse;   

DOI  :  10.7554/eLife.11102

来源: DOAJ

【 摘 要 】

A new mutant mouse (lamb1t) exhibits intermittent dystonic hindlimb movements and postures when awake, and hyperextension when asleep. Experiments showed co-contraction of opposing muscle groups, and indicated that symptoms depended on the interaction of brain and spinal cord. SNP mapping and exome sequencing identified the dominant causative mutation in the Lamb1 gene. Laminins are extracellular matrix proteins, widely expressed but also known to be important in synapse structure and plasticity. In accordance, awake recording in the cerebellum detected abnormal output from a circuit of two Lamb1-expressing neurons, Purkinje cells and their deep cerebellar nucleus targets, during abnormal postures. We propose that dystonia-like symptoms result from lapses in descending inhibition, exposing excess activity in intrinsic spinal circuits that coordinate muscles. The mouse is a new model for testing how dysfunction in the CNS causes specific abnormal movements and postures.

【 授权许可】

Unknown