Differences in lumbar motor neuron pruning in an animal model of early onset spasticity

Author:

Brandenburg Joline E.12ORCID,Gransee Heather M.3,Fogarty Matthew J.45,Sieck Gary C.143

Affiliation:

1. Department of Physical Medicine and Rehabilitation, Mayo Clinic College of Medicine, Rochester, Minnesota

2. Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota

3. Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota

4. Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota

5. School of Biomedical Sciences, The University of Queensland, Brisbane, Australia

Abstract

Motor neuron (MN) development in early onset spasticity is poorly understood. For example, spastic cerebral palsy (sCP), the most common motor disability of childhood, is poorly predicted by brain imaging, yet research remains focused on the brain. By contrast, MNs, via the motor unit and neurotransmitter signaling, are the target of most therapeutic spasticity treatments and are the final common output of motor control. MN development in sCP is a critical knowledge gap, because the late embryonic and postnatal periods are not only when the supposed brain injury occurs but also are critical times for spinal cord neuromotor development. Using an animal model of early onset spasticity [ spa mouse (B6.Cg- Glrbspa/J) with a glycine (Gly) receptor mutation], we hypothesized that removal of effective glycinergic neurotransmitter inputs to MNs during development will influence MN pruning (including primary dendrites) and MN size. Spa (Glrb−/−) and wild-type (Glrb+/+) mice, ages 4–9 wk, underwent unilateral retrograde labeling of the tibialis anterior muscle MNs via peroneal nerve dip in tetramethylrhodamine. After 3 days, mice were euthanized and perfused with 4% paraformaldehyde, and the spinal cord was excised and processed for confocal imaging. Spa mice had ~61% fewer lumbar tibialis anterior MNs ( P < 0.01), disproportionately affecting larger MNs. Additionally, a ~23% reduction in tibialis anterior MN somal surface area ( P < 0.01) and a 12% increase in primary dendrites ( P = 0.046) were observed. Thus MN pruning and MN somal surface area are abnormal in early onset spasticity. Fewer and smaller MNs may contribute to the spastic phenotype. NEW & NOTEWORTHY Motor neuron (MN) development in early onset spasticity is poorly understood. In an animal model of early onset spasticity, spa mice, we found ~61% fewer lumbar tibialis anterior MNs compared with controls. This MN loss disproportionately affected larger MNs. Thus number and heterogeneity of the MN pool are decreased in spa mice, likely contributing to the spastic phenotype.

Funder

HHS | NIH | National Heart, Lung, and Blood Institute (NHBLI)

HHS | NIH | National Institute on Aging (U.S. National Institute on Aging)

Australian National Health & Medical Research Council

HHS | NIH | National Center for Advancing Translational Sciences (NCATS)

Mayo Clinic Children's Research Center

Publisher

American Physiological Society

Subject

Physiology,General Neuroscience

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