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.

Public Health Relevance

NMDA receptors (NMDARs) play an important role in excitatory neurotransmission and require D-serine and glycine as coagonists in addition to glutamate. Using experimental tools that we have developed, we want to study the role of the glycine-degrading enzyme glycine decarboxylase (GLDC), which is expressed in astrocytes, a cell type in the nervous system that has been linked to phasic activation of NMDARs in excitatory neurotransmission, so far in the amygdala. As deficits of NMDAR function have been proposed to contribute to cognitive deficits and psychosis, elucidating mechanisms by which modulation of glycine breakdown in astrocytes affects excitatory neurotransmission will contribute to a better understanding of physiological homeostatic mechanisms controlling neuronal activity and eventually to the development of novel therapies.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
High Priority, Short Term Project Award (R56)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Nadler, Laurie S
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University of Illinois Urbana-Champaign
Veterinary Sciences
Schools of Veterinary Medicine
United States
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