Structure-Function and Behavioral Studies on the Glutamate Delta-1 Receptor

Abstract

The delta family of ionotropic glutamate receptors (iGluRs) consists of glutamate delta-1 (GluD1) and glutamate delta-2 (GluD2) receptors. The function of GluD1 in the central nervous system (CNS) remains elusive. As a first step we conducted electrophysiological studies on the rat clone of GluD1 to study the activation gate and ligand binding domain of GluD1 receptor. Site directed mutagenesis in the SYTANLAAF region resulted in four constitutively open mutants GluD1A650C, GluD1L652A, GluD1A654C, and GluD1F655A. Channel blockers pentamidine and NASP inhibited currents through the GluD1 mutant receptors. D-serine and extracellular calcium had opposing effects on GluD1 mutants and a chimeric GluD1-D2 lurcher. D-serine decreased currents through GluD1F655A and chimeric GluD1-D2 lurcher while calcium increased currents through GluD1F655A. These results suggest, GluD1 receptors have a conserved activation gate. In addition conformational changes brought about by D-serine and calcium are conserved among GluD1 and GluD2 receptors. GluD1 functions in synapse formation. Addtionally the GRID1 gene has been implicated in neuropsychiatric disorders. We hypothesize that synaptic abnormalities due to GluD1 deletion would lead to aberrant behaviors. Thus we performed tests in GluD1 knockout (GluD1 KO) mice to study the functional significance of the GluD1 receptor. GluD1 KO mice showed hyperactivity, lower anxiety-like behavior, hyperaggression, depression-like behavior, and social interaction deficits. Altered levels of synaptic proteins and iGluR subunits were seen in prefrontal cortex and amygdala. Few aberrant behaviors were rescued by chronic lithium and D-cycloserine (DCS) treatment. Amygdala functions in associative fear learning while prefrontal cortex plays a role in working memory. We found molecular abnormalities in amygdala and prefrontal cortex. Thus we tested the effect of GluD1 deletion on amygdalar and prefrontal cortex associated learning tasks. We observed normal or enhanced learning for prefrontal cortex associated tasks. However we found deficits in fear learning. iGluR expression was altered in the hippocampus along with synaptic anomalies in the amygdala, prefrontal cortex and hippocampus. These data suggest GluD1 functions in regulation of behavior and synaptic physiology. In addition GluD1 KO mice manifest symptoms related to neuropsychiatric disorders with which GRID1 has been associated.