Glia Get a GRIP on Neurons

Abstract

The migration of cerebellar granule cells during brain development requires stimulation of their N -methyl-D-aspartate (NMDA) receptors by glutamate and either D-serine or glycine. They are guided by radial glia cells, although this intercellular relationship does not appear to require conventional synapse formation. Kim et al. report that production of D-serine by serine racemase in Bergmann glia cells constitutes a chemokinetic signaling mechanism that controls granule cell migration in the cerebellum. D-serine is generated in glia after activation of the AMPA receptors by glutamate. Using a two-hybrid screen, the authors determined that serine racemase binds to a PDZ domain of the glutamate receptor interacting protein (GRIP). GRIP associates with activated AMPA receptors in glia. Endogenous GRIP, AMPA receptor, and serine racemase were detected in cultures of primary glia. Stimulation of the AMPA receptors in cultured glia increased the secretion of D-serine, whereas treatment with an AMPA receptor antagonist blocked basal production of D-serine. Overexpression of the GRIP PDZ domain in either cultured glia or in cerebellar glia cells of postnatal mice increased D-serine production, even in the absence of AMPA receptor activation. Treatment of mice cerebellar slices with either an inhibitor of serine racemase or an enzyme that degrades D-serine reduced granule cell migration by 60%. The authors suggest that activation of AMPA receptors on Bergmann glia by glutamate results in the association of GRIP with serine racemase. The enzyme then generates D-serine that is released to act, in concert with glutamate, on NMDA receptors on granule cells. Thus, rather than relying on conventional synaptic communication, Bergmann glia regulate neuronal migration by releasing D-serine as a neuromodulator. P. M. Kim, H. Aizawa, P. S. Kim, A. S. Huang, S. R. Wickramasinghe, A. H. Kashani, R. K. Barrow, R. L. Huganir, A. Ghosh, S. H. Snyder, Serine racemase: Activation by glutamate neurotransmission via glutamate receptor interacting protein and mediation of neuronal migration. Proc. Natl. Acad. Sci. U.S.A. 102 , 2105-2110 (2005). [Abstract] [Full Text]