Genetic Control of Glutamate Receptor Function

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DESCRIPTION (provided by applicant): The abundance of GluR2 mRNA relative to other AMPA receptor subunit mRNAs is highly variable in many GABAergic interneurons, which endows them with a wide spectrum of AMPA receptor properties. GluR2 mRNA and protein levels decline following intense seizure activity or transient ischemia in certain vulnerable neuron populations before clear histological signs of cell damage, raising the possibility that larger synaptic currents or excess calcium entry through newly synthesized GluR2-deficient AMPA synaptic receptors contributes to the later phase of neuron damage. There is evidence for activity-dependent local dendritic translation of GluR2 mRNA, and for postsynaptic GluR2 translation following LTP stimuli. All of these findings indicate that the mechanisms responsible for moderate changes in GluR2 expression - developmentally, during synaptic plasticity, and after seizures or traumatic insult in the adult - are important neuronal regulatory controls governing synaptic phenotype. Work in the current project period has identified specific transcriptional and translational regulatory mechanisms operating on AMPA receptor genes. In the proposed work we intend to test the following hypotheses: i) that translational regulation of GluR2 mRNA requires one or more of the multiple conserved cytoplasmic polyadenylation elements (CPE) or polyadenylation response elements (PRE) resident in the 3'UTR; ii) that MAP kinase pathways exert dual control over translation of GluR2 transcripts; iii) that neuron-dependent transcriptional start site selection influences the form and extent of translational control by 5' and 3'UTR; and iv) that repression of GluR2 expression by seizures requires the RE1 silencer in the GluR2 promoter. Regulation of the physiological properties of glutamate receptor channels at the translational and transcriptional levels should be relevant to the late phase of LTP, learning, and the response to seizures, as well as other situations in which receptor phenotype is remodeled .