Objective: A mouse model that exhibits symptoms appropriate to dystonia will allow investigation underlying circuit abnormalities. Here we tested two hypotheses with the lamb1t mouse: whether circuits that produce antagonist muscle co-contraction are in brain or spinal cord, and whether the mutation alters firing in two neurons that express the mutated protein.

Background: A mouse with intermittent and stress-enhanced hindlimb hyperextension has dominant inheritance. Locus mapping and exome sequencing identified a nonsense mutation that truncates the end of the laminin beta1 subunit. The truncated protein is expressed. Laminins are known to have roles in synapse structure and plasticity, a credible basis for a neurological disorder. Lamb1 is expressed in discrete neuronal populations including dorsal horn, striatum, and cerebellum, but not universally.

Methods: Behavioral tests, peripheral nerve assessment, electromyography, acute spinal transection, and awake recordings from Purkinje and deep cerebellar neurons.

Results: Symptoms appeared by weaning, worsened over months, and plateaued. Mild stress induced hindlimb hyperextension, but the mice had normal motor control when unstressed, and ran on wheels in the dark. Motor abnormalities were quantified by beam, Rotarod, and Olympic pool tests. Reflexes and nerve conduction velocity ruled out peripheral neuropathy. However, twitching of the hindlimbs was often seen in sleep and anesthesia, produced by co-contraction. To test whether this patterned activity originated in brain, spinal transection was performed under anesthesia: the activity persisted and even increased, indicating hyperactive spinal circuits. To test the hypothesis that neuronal activity is altered, we recorded from Lamb1-expressing Purkinje cells and neurons in the deep cerebellar nuclei. Both fired irregularly during abnormal movements, but not when they were absent.

Conclusions: The intermittency of symptoms when awake indicates that the brain can suppress the hyperactive spinal circuits. We propose that lapses of descending inhibitory information originating in classic dystonia circuits allow the symptoms to manifest, and conversely, that abnormal regulation of spinal circuits is the proximal cause of co-contraction. Further work is needed to investigate the effects of the mutation on other dystonia circuits.

« Back to 2016 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/symptoms-of-dystonia-in-a-mouse-with-mutation-in-lamb1/