NEUREGULIN-BETA INDUCES EXPRESSION OF AN NMDA-RECEPTOR SUBUNIT

Neuregulins (also known as ARLA, NDF, heregulin, GGF) are a family of widely expressed growth and differentiation factors. Neuregulins secre ted from motor neurons accumulate at maturing neuromuscular junctions, where they stimulate transcription of genes encoding specific acetylc holine receptors. How these factors function at central synapses, howe ver, is unknown. In the maturing cerebellum, neuregulins are concentra ted in glutamatergic messy fibres that innervate granule cells in the internal granule-cell layer(1). We have analysed the effects of neureg ulins on the expression of genes encoding NMDA (N-methyl-D-aspartate) receptors in the cerebellum, because receptor composition changes dram atically as expression of the receptor NR2C subunit is specifically in duced in neurons in the internal granule-cell layer during synaptogene sis. Here we report that addition of a neuregulin-beta isoform to cult ured cerebellar slices specifically increases the expression of NR2C m essenger RNAs by at least 100-fold; effects are only minor with a neur egulin-alpha isoform. This stimulation of NR2C expression requires syn aptic activity by NMDA receptors, as well as neuregulin-beta. Addition of the NMDA-receptor-channel blocker AP-5 prevents upregulation of th e NR2C subunit by neuregulin, whereas an AMPA/kainate-receptor antagon ist does not. Consistent with these effects of neuregulin, we find tha t granule cells express its receptors ErbB2 and ErbB4 before the NR2C subunit of the NMDA receptor. Our results indicate that neuregulins re gulate the composition of neurotransmitter receptors in maturing synap ses in the brain, in a manner analogous to the neuromuscular junction.