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

Yi Bessie Liu,Johnny Salameh,Kathleen J Sweadner,Allison Brashear,Ambika Tewari,Elena Arystarkhova,Laurie J Ozelius,Kamran Khodakhah,Thomas G Hampton

doi:10.7554/elife.11102

Abstract

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.

Highlights

Dystonia, the third-most common human movement disorder, involves ’sustained or intermittent muscle contractions causing abnormal, often repetitive movements, postures or both’ (Albanese et al, 2013)
The average firing rate was decreased in the deep cerebellar nuclei (DCN) in the mutant during abnormal postures, whereas there was no significant difference between the wild type (WT) and the mutant during normal postures (Figure 8B)
Laminin b1 is present in the extracellular matrix (ECM) in many tissues and in different subunit isoform combinations, each laminin composed of one a, one b, and one g subunit

Summary

Introduction

The third-most common human movement disorder, involves ’sustained or intermittent muscle contractions causing abnormal, often repetitive movements, postures or both’ (Albanese et al, 2013). There is strong evidence that dystonia is a circuit disorder involving various brain regions, including sensory input, premotor and motor cortex, striatum and globus pallidus, subthalamic nucleus and parts of the thalamus, cerebellum, and the tracts connecting them (Berardelli et al, 1998; Breakefield et al, 2008; Lehericy et al, 2013; Neychev et al, 2011; Quartarone and Hallett, 2013; Thompson et al, 2011). There is little certainty about exactly how circuit and synaptic abnormalities produce the persistent overflow of motor control, often involving only certain muscle groups and the co-contraction of opposing muscles.

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Conclusion