Mammalian biology is stereospecific with D-sugars and L-amino acids predominating. Recently substantial concentrations of D-serine, D-aspartate and, to a lesser extent, D-alanine have been identified in mammalian brain with D-serine levels of about 0.3 mM, one-third of the L-serine concentration. In the past decade, researchers have definitively demonstrated that D-serine, but not glycine, is an endogenous ligand for synaptic NMDA receptors (NMDARs) in the cortex and the hippocampus, thereby overthrowing the long-standing dogma that glutamate and glycine are the physiological ligands of the NMDAR. D-serine is also implicated in schizophrenia as the serum and CSF level of D-serine has been reported to be significantly lower in schizophrenic patients than healthy controls. Presumably, D-serine works through the glutamate hypothesis of schizophrenia, which in its simplest form, suggests that hypoactivity of the NMDAR contributes to the pathophysiology of schizophrenia. Disrupted-In-Schizophrenia-1 (DISC1), originally discovered in a Scottish family with high incidence of schizophrenia, bipolar disorder and major depression, is among the first genes to be definitively linked to major psychiatric illnesses. Thus perturbation of DISC1 and D-serine/NMDA receptor hypofunction are viewed as two prominent but independent risk factors of schizophrenia. Here we demonstrate that these two pathways intersect with behavioral consequences. DISC1 binds to and stabilizes serine racemase (SR), the enzyme that generates D-serine. Mutant DISC1 fails to bind to SR, facilitating ubiquitination and degradation of SR and a decrease in D-serine production. In a mouse model of selective and inducible expression of mutant DISC1 in astrocytes, expression of mutant DISC1 decreases protein but not mRNA levels of SR, resulting in diminished production of D-serine. Adult mice with life-long expression of mutant DISC1 exhibit behavioral abnormalities consistent with hypofunction of NMDA neurotransmission. These findings support a model wherein mutant DISC1 leads to SR degradation via dominant-negative effects, resulting in D-serine deficiency that diminishes NMDA neurotransmission thus linking DISC1 and NMDA pathophysiologic mechanisms in mental illness.One interesting observation is that the effect of mutant DISC1 on SR seems to be specific to astrocytes. Furthermore, the relative abundance of D-serine and SR in neurons vs. glia has been a controversy in the field for many years. Using transgenic mice expressing eGFP under the SR promoter as well as mice with targeted deletion of SR, we demonstrate predominantly neuronal sources of D-serine dependent on astrocytic supply of L-serine in the cortex and the hippocampus.These findings clarify the cellular basis for the regulation of NMDAR neurotransmission by D-serine.As SR is a relatively recently identified enzyme, there have been few studies of its interactions with synaptic proteins. Through a protein array screening approach, we demonstrate that SR interacts with synaptic proteins--- postsynaptic density protein 95 (PSD-95) and stargazin, forming a ternary complex. Binding to stargazin facilitates the cell membrane localization of SR and inhibits its activity. We propose that by physically interacting with synaptic proteins, the enzymatic activity as well as the intracellular localization of SR could be dynamically regulated, potentially leading to a coupling of the activity of NMDA and AMPA receptors. It could play a role in the regulation of brain functions under physiological and pathological conditions via the production of the neuromodulator D-serine.
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The Novel Role of D-serine in Synaptic Transmission and Psychiatric Disorders
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