Valproic acid blocks excitability in SMA type I mouse motor neurons.
Valproic acid (VPA), an antiepileptic drug and HDAC inhibitor, has been identified as a drug candidate for spinal muscular atrophy (SMA), a motoneuron disorder for which currently no effective therapy is available. Based on its potential to up-regulate SMN expression from the SMN2 gene in fibroblasts and lymphoblastoid cell lines from SMA patients, we analysed the effects of VPA in isolated motoneurons from Smn(-/-);SMN2 mice, a model for SMA type I. Treatment with VPA increased Smn expression but unexpectedly also led to reduced growth cone size and reduced excitability in axon terminals of mutant motoneurons. Analysis of Ca2+ currents and distribution of voltage-gated Ca2+ channels revealed an inhibitory function of VPA on voltage-gated Ca2+ channels and possibly also other ion channels that contribute to presynaptic excitability of motoneurons. Our data indicate effects of VPA which might aggravate disease-specific symptoms in SMA patients.
Rak
Kristen
K
Institute for Clinical Neurobiology, University of Wuerzburg, Josef-Schneider-Str. 11, D-97080 Wuerzburg, Germany.
Lechner
Barbara Dorothea
BD
Schneider
Christine
C
Drexl
Hans
H
Sendtner
Michael
M
Jablonka
Sibylle
S
D000199:Actins / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology*; D001369:Axons / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D020439:Growth Cones / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000187:drug effects* / Q000502:physiology*; D009414:Nerve Growth Factors / Q000378:metabolism; D014897:Spinal Muscular Atrophies of Childhood / Q000188:drug therapy* / Q000503:physiopathology*; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism; D014635:Valproic Acid / Q000008:administration & dosage / Q000494:pharmacology*
D000199:Actins; D000927:Anticonvulsants; D015220:Calcium Channels; D009414:Nerve Growth Factors; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D014635:Valproic Acid; D002118:Calcium