Abstract：
:In spinal muscular atrophy, a neurodegenerative disease caused by ubiquitous deficiency in the survival motor neuron (SMN) protein, sensory-motor synaptic dysfunction and increased excitability precede motor neuron (MN) loss. Whether central synaptic dysfunction and MN hyperexcitability are cell-autonomous events or they contribute to MN death is unknown. We addressed these issues using a stem-cell-based model of the motor circuit consisting of MNs and both excitatory and inhibitory interneurons (INs) in which SMN protein levels are selectively depleted. We show that SMN deficiency induces selective MN death through cell-autonomous mechanisms, while hyperexcitability is a non-cell-autonomous response of MNs to defects in pre-motor INs, leading to loss of glutamatergic synapses and reduced excitation. Findings from our in vitro model suggest that dysfunction and loss of MNs result from differential effects of SMN deficiency in distinct neurons of the motor circuit and that hyperexcitability does not trigger MN death.
journal_name
Cell Repjournal_title
Cell reportsauthors
Simon CM,Janas AM,Lotti F,Tapia JC,Pellizzoni L,Mentis GZdoi
10.1016/j.celrep.2016.06.087subject
Has Abstractpub_date
2016-08-02 00:00:00pages
1416-1430issue
5issn
2211-1247pii
S2211-1247(16)30856-7journal_volume
16pub_type
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