Motor circuit dysfunction in a Drosophila model of Spinal Muscular Atrophy

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• Dr. Wendy Imlach, Center for Motor Neuron Biology and Disease, Department of Physiology and Cellular Biophysics, Columbia University, New York
• Thursday 28 October 2010, 16:00-17:00
• Hodgkin Huxley Seminar Room, Physiology Building, Downing Site.

If you have a question about this talk, please contact Christian Scheppach.

Spinal Muscular Atrophy (SMA) is a devastating disease of the spinal cord, which results in the atrophy of proximal limb and trunk muscles. It is the second most common autosomal recessive genetic disease in humans and the most common genetic cause of infant mortality. SMA is caused by reduced levels of the Survival of Motor Neuron (SMN) protein, a component of a macromolecular complex that is required for the assembly of small nuclear ribonucleoproteins, essential components of the pre-mRNA splicing machinery.

We have analyzed Drosophila mutants of SMN for SMA related phenotypes. We have found that muscle size and locomotor activity are significantly impaired and these animals have defective motor circuit pattern activity. However when we examined neurotransmitter release at the neuromuscular junction (NMJ), we found a surprising increase in the amount of neurotransmitter released. Furthermore, by inhibition or rescue of SMN in specific neuronal types in the motor circuit, we have found that this increase is not due to a requirement for SMN in motor neurons themselves, but instead is elicited by defective synaptic input from cholinergic interneurons, which in turn induces motor neuron hyperexcitability. We have further found that inhibition of K+ channels in cholinergic interneurons of SMN mutants, or treatment with K+ channel pharmacological antagonists can restore normal NMJ neurotransmission in SMN mutants.

To identify molecules disrupted in the motor circuits of SMN mutants, we carried out a screen for genes with defective pre-mRNA splicing. From this effort, we have identified a novel evolutionarily conserved trans-membrane protein, stasimon, with reduced expression in SMN mutants. We show that restoring this protein in the cholinergic interneurons of SMN mutants reinstates normal neurotransmitter release from motor neurons. Our data reveals that cholinergic interneurons are an essential cellular site of action for SMN in Drosophila and show that restoration of normal physiological motor circuit activity ameliorates many deficits in this model of Spinal Muscular Atrophy.

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