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SUMMARY:Motor circuit dysfunction in a Drosophila model of Spinal Muscular
  Atrophy - Dr. Wendy Imlach\, Center for Motor Neuron Biology and Disease\
 , Department of Physiology and Cellular Biophysics\, Columbia University\,
  New York
DTSTART:20101028T150000Z
DTEND:20101028T160000Z
UID:TALK27581@talks.cam.ac.uk
CONTACT:Christian Scheppach
DESCRIPTION:Spinal Muscular Atrophy (SMA) is a devastating disease of the 
 spinal cord\, which results in the atrophy of proximal limb and trunk musc
 les. It is the second most common autosomal recessive genetic disease in h
 umans and the most common genetic cause of infant mortality. SMA is caused
  by reduced levels of the Survival of Motor Neuron (SMN) protein\, a compo
 nent of a macromolecular complex that is required for the assembly of smal
 l nuclear ribonucleoproteins\, essential components of the pre-mRNA splici
 ng machinery. \n\nWe have analyzed _Drosophila_ mutants of SMN for SMA rel
 ated phenotypes. We have found that muscle size and locomotor activity are
  significantly impaired and these animals have defective motor circuit pat
 tern activity. However when we examined neurotransmitter release at the ne
 uromuscular 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 int
 erneurons\, which in turn induces motor neuron hyperexcitability. We have 
 further found that inhibition of K+ channels in cholinergic interneurons o
 f SMN mutants\, or treatment with K+ channel pharmacological antagonists c
 an restore normal NMJ neurotransmission in SMN mutants.\n\nTo identify mol
 ecules disrupted in the motor circuits of SMN mutants\, we carried out a s
 creen for genes with defective pre-mRNA splicing. From this effort\, we ha
 ve identified a novel evolutionarily conserved trans-membrane protein\, st
 asimon\, with reduced expression in SMN mutants. We show that restoring th
 is protein in the cholinergic interneurons of SMN mutants reinstates norma
 l neurotransmitter release from motor neurons. Our data reveals that choli
 nergic interneurons are an essential cellular site of action for SMN in _D
 rosophila_ and show that restoration of normal physiological motor circuit
  activity ameliorates many deficits in this model of Spinal Muscular Atrop
 hy. \n
LOCATION:Hodgkin Huxley Seminar Room\, Physiology Building\, Downing Site
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