GEPHYRIN ANTISENSE OLIGONUCLEOTIDES PREVENT GLYCINE RECEPTOR CLUSTERING IN SPINAL NEURONS

EACH neuron in the mammalian brain carries many postsynaptic membrane specializations containing high densities of receptors that mediate signal transduction upon neurotransmitter release from the apposed nerve terminal1. Little is known about the mechanisms by which receptors are transported to and anchored at postsynaptic sites, but extracellular2 as well as intracellular3 components may be involved. Ultrastructural studies have shown that the peripheral membrane protein gephyrin4, Which co-purifies with the postsynaptic inhibitory glycine receptor (GlyR) upon affinity chromatography5,6, is situated on the cytoplasmic face of glycinergic postsynaptic membranes7-9. Moreover, gephyrin binds with high affinity to polymerized tubulin and has been postulated to link the GlyR to the subsynaptic cytoskeleton10. Here we report that treatment of rat spinal neurons in culture with gephyrin antisense oligonucleotides prevents the formation of GlyR clusters in the dendritic plasma membrane. Thus, gephyrin is essential for localizing the GlyR to presumptive postsynaptic plasma membrane specializations.