Characterization of NMJ deficits in a mild SMA mouse model.


Pre-Clinical Research

Poster Number: 280


Tyler Tarr, PhD, University of Pittsburgh, Chris Yang, BS, University of Pittsburgh, Stephen Meriney, PhD, University of Pittsburgh

Spinal muscular atrophy (SMA) is a disease caused by a reduction in overall levels of the survival motor neuron (SMN) protein, specifically caused by mutation of the SMN1 gene. The SMN2 gene can only partially rescue the absence of SMN protein due to exon skipping, and varying copy numbers of SMN2 across the patient population leads to a spectrum of disease severity. Patients with multiple copies of SMN2 have a mild form of SMA, but although patients with mild SMA have a better prognosis, they still experience debilitating symptoms that require treatment.

To understand the pathophysiology and progression of mild SMA and test novel treatments, we have begun characterizing a mild SMA mouse model (2B/2B-Neo) using a combination of electrophysiology, behavioral assays, and immunohistochemistry.

In recordings of ex vivo nerve-muscle preparations from this mouse model, we found no discernible change in the quantal content of neurotransmitter release compared to littermate controls (although there were increases in mEPP and EPP amplitude). There was also a significant increase in short-term depression in response to 50 Hz stimulus trains. These changes are reminiscent of neuromuscular synapses undergoing homeostatic plasticity to compensate for a disease-mediated deficit. We also found deficits in multiple behavioral parameters related to strength and gait. Finally, using immunohistochemistry, we found substantial structural changes in the overall shape of the neuromuscular junction (NMJ) and the pattern of neurofilament staining in muscles from the mild SMA model mice.

Our results show this mild SMA model displays both structural and functional deficits at the NMJ. We are currently testing the effects of novel treatment approaches hypothesized to provide trophic support for these neuromuscular synapses.