Purkinje cell dysfunction and alteration of long-term synaptic plasticity in fetal alcohol syndrome.
In cerebellum and other brain regions, neuronal cell death because of ethanol consumption by the mother is thought to be the leading cause of neurological deficits in the offspring. However, little is known about how surviving cells function. We studied cerebellar Purkinje cells in vivo and in vitro to determine whether function of these cells was altered after prenatal ethanol exposure. We observed that Purkinje cells that were prenatally exposed to ethanol presented decreased voltage-gated calcium currents because of a decreased expression of the gamma-isoform of protein kinase C. Long-term depression at the parallel fiber-Purkinje cell synapse in the cerebellum was converted into long-term potentiation. This likely explains the dramatic increase in Purkinje cell firing and the rapid oscillations of local field potential observed in alert fetal alcohol syndrome mice. Our data strongly suggest that reversal of long-term synaptic plasticity and increased firing rates of Purkinje cells in vivo are major contributors to the ataxia and motor learning deficits observed in fetal alcohol syndrome. Our results show that calcium-related neuronal dysfunction is central to the pathogenesis of the neurological manifestations of fetal alcohol syndrome and suggest new methods for treatment of this disorder.
Servais
Laurent
L
Laboratory of Neurophysiology, Université Libre de Bruxelles (ULB), B-1070 Brussels, Belgium. laurent.servais@rdb.aphp.fr
Hourez
Raphaël
R
Bearzatto
Bertrand
B
Gall
David
D
Schiffmann
Serge N
SN
Cheron
Guy
G
D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000503:physiopathology*; D007150:Immunohistochemistry; D017774:Long-Term Potentiation / Q000187:drug effects; D051379:Mice; D009473:Neuronal Plasticity / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D011247:Pregnancy; D011493:Protein Kinase C / Q000378:metabolism; D011689:Purkinje Cells / Q000187:drug effects*; D045442:Rotarod Performance Test; D013569:Synapses / Q000187:drug effects*
D015220:Calcium Channels; D000431:Ethanol; C087857:protein kinase C gamma; D011493:Protein Kinase C; D002118:Calcium