Though etiological mechanisms underlying schizophrenia remain largely unknown, a convergence of pharmacologic and genetic data implicates a dysregulation of N-methyl-D-aspartate receptor (NMDAR) function. NMDARs are ligand-gated ion channels that play critical roles in neurodevelopment and synaptic plasticity and subtle changes in NMDAR functioning can have wide-ranging developmental and cognitive effects. Thus, there is a critical need for a detailed understanding of the molecular mechanisms involved in the regulation of NMDARs which will yield insights into the pathophysiology of schizophrenia and facilitate the development of novel therapeutic strategies. Unlike all other neurotransmitter receptors, NMDARs have an absolute requirement for the binding of two different agonists in order to be activated. In addition to glutamate released from the presynaptic terminal, NMDARs require a co-agonist, which can be either glycine or D-serine. At most forebrain synapses, D-serine is the primary NMDAR co-agonist and D-serine deficiency has been implicated in the pathophysiology of schizophrenia. However, our understanding of the mechanisms regulating the availability of synaptic D-serine remains quite limited. Even the cellular source of D-serine is fiercely debated. D-serine is synthesized in the brain by the enzyme serine racemase (SR) that converts L-serine to D-serine. Original studies placed both SR and D-serine in astrocytes, and activity-dependent release of D-serine from astrocytes was venerated as the prototypical gliotransmitter. However, a growing literature using more selective antibodies and mouse genetics has challenged this astrocytic role in D-serine regulation and pointed to a primarily neuronal source. In this proposal, conditional SR knock-out mice were injected with viral constructs into the hippocampus to remove SR in only a few individual neurons. By comparing the effects of SR deletion to adjacent control neurons, we have obtained preliminary data that provides the first rigorously- controlled evidence for a functional role of neuronal D-serine. This preliminary data supports our central hypothesis that synaptic NMDAR activity and function is regulated by postsynaptic SR and D-serine release.
In Specific Aim 1, the cell-autonomous effects of postsynaptic SR deletion will be characterized and the source of the remaining synaptic co-agonist will be determined.
In Specific Aim 2, we will examine in detail the effects of postsynaptic SR deletion on both postsynaptic and presynaptic NMDARs.
In Specific Aim 3, we will determine the functional role of postsynaptic SR, using an innovative molecular replacement approach to replace endogenous SR with characterized recombinant SR mutants to explore the function and regulation of postsynaptic SR. Successful completion of this research program will provide a better understanding of the molecular mechanisms regulating co-agonist availability at synaptic NMDARs, and how these processes might be disrupted in disease states, helping to lead towards our long-term goal of developing novel disease-modifying approaches to treat schizophrenia and other complex neuropsychiatric disorders.

Public Health Relevance

Though the underlying causes of schizophrenia are poorly understood, accumulating evidence has implicated abnormalities in the function of NMDA receptors which are important for the development and adaptability of neuronal connections. This proposal aims to use an innovative approach to understand the function of a neuronal enzyme, called serine racemase, which is critically involved in the regulation of NMDA receptors. Understanding how serine racemase regulates NMDA receptors will provide critical insights that may facilitate the development of novel, disease-modifying approaches for the treatment of schizophrenia.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Nadler, Laurie S
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University of California Davis
Schools of Medicine
United States
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