Role of glycine decarboxylase in regulating NMDA receptor function

University Of Illinois At Urbana-Champaign, Urbana IL

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Abstract

PROJECT SUMMARY / ABSTRACT NMDA receptors (NMDARs) require two agonists for activation: glutamate, binding to the NR2 subunit, and glycine (or D-serine), binding to the glycine modulatory site (GMS) on the NR1 subunit. The identity of the NMDA receptor coagonist can to some degree be synapse-specific: whereas in the hippocampus at the SC-CA1 synapse D-serine is the preferred coagonist, at the mPP-DG synapse glycine is the preferred coagonist. Glycine could be accumulated by astrocytes, which express the glycine transporter GlyT1, and be released through the mechanism of reverse transport in response to increases in the intra-astrocyte Na+ concentration resulting from activation of glial AMPA receptors. D-serine is released from neurons through a non-vesicular release mechanism. In the amygdala, D-serine was found to be present ambiently, providing tonic activation of NMDARs, whereas glycine could be released in an activity-dependent manner, thus providing conditions for phasic activation of NMDARs. Notably, knowledge of the functional roles of endogenous glycine is limited. Glycine is degraded in astrocytes by the enzyme glycine decarboxylase (GLDC). In this project, in order to analyze the function of endogenous glycine under physiological conditions, we want to study mice in which the entire 9p24.1 chromosomal region containing the Gldc gene or only the Gldc gene are triplicated, i.e., present in four instead of the normal two copies. Specifically, we want to test the hypothesis that increased glycine cleavage in astrocytes, which likely leads to decreased intracellular glycine levels in astrocytes, results in reduced release from glycine from astrocytes following afferent activation via AMPA receptors, thus resulting in NMDA receptor hypofunction and deficits in synaptic functions. We will also analyze how presumably decreased glycine levels affect NMDAR-dependent biochemical pathways and behaviors.