Targeted disruption of serine racemase affects glutamatergic neurotransmission and behavior

Department of Psychiatry, Harvard Medical School, Belmont, MA 02478, USA.
Molecular Psychiatry (Impact Factor: 15.15). 09/2010; 15(11):1122-1122. DOI: 10.1038/mp.2010.84

ABSTRACT A subset of glutamate receptors that are specifically sensitive to the glutamate analog N-methyl-D-aspartate (NMDA) are molecular coincidence detectors, necessary for activity-dependent processes of neurodevelopment and in sensory and cognitive functions. The activity of these receptors is modulated by the endogenous amino acid D-serine, but the extent to which D-serine is necessary for the normal development and function of the mammalian nervous system was previously unknown. Decreased signaling at NMDA receptors has been implicated in the pathophysiology of schizophrenia based on pharmacological evidence, and several human genes related to D-serine metabolism and glutamatergic neurotransmission have been implicated in the etiology of schizophrenia. Here we show that genetically modified mice lacking the ability to produce D-serine endogenously have profoundly altered glutamatergic neurotransmission, and relatively subtle but significant behavioral abnormalities that reflect hyperactivity and impaired spatial memory, and that are consistent with elevated anxiety.

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    ABSTRACT: D-Serine, an endogenous coagonist of the N-methyl-D-aspartate receptor (NMDAR), is widely distributed in the central nervous system and is synthesized from L-serine by serine racemase (SR). NMDAR plays an important role in pain processing including central sensitization that eventually causes hyperalgesia. To elucidate the roles of D-serine and SR in pain transmission, we evaluated the behavioral changes and spinal nociceptive processing induced by formalin using SR knock-out (KO) mice. We found that SR is mainly distributed in lamina II of the dorsal horn of the spinal cord in wild-type (WT) mice. Although the formalin injected subcutaneously induced the biphasic pain response of licking in SR-KO and WT mice, the time spent on licking was significantly longer in the SR-KO mice during the second phase of the formalin test. The number of neurons immunopositive for c-Fos and phosphorylated extracellular signal-regulated kinase (p-ERK), which are molecular pain markers, in laminae I-II of the ipsilateral dorsal horn was significantly larger in the SR-KO mice. Immunohistochemical staining revealed that the distribution of SR changed from being broad to being concentrated in cell bodies after the formalin injection. On the other hand, the expression level of the cytosolic SR in the ipsilateral dorsal horn significantly decreased. Oral administration of 10 mM D-serine in drinking water for one week cancelled the difference in pain behaviors between WT and SR-KO mice in phase 2 of the formalin test. These findings demonstrate that the SR-KO mice showed increased sensitivity to inflammatory pain and the WT mice showed translocation of SR and decreased SR expression levels after the formalin injection, which suggest a novel antinociceptive mechanism via SR indicating an important role of D-serine in pain transmission.
    PLoS ONE 08/2014; 9(8):e105282. · 3.53 Impact Factor
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    ABSTRACT: D-serine, an endogenous co-agonist for the glycine site of the synaptic NMDA glutamate receptor, regulates synaptic plasticity and is implicated in schizophrenia. Serine racemase (SR) is the enzyme that converts L-serine to D-serine. In this study, we demonstrate that SR interacts with the synaptic proteins── postsynaptic density protein 95 (PSD-95) and stargazin, forming a ternary complex. SR binds to the PDZ3 domain of PSD-95 through the PDZ domain ligand at its C-terminus. SR also binds to the C-terminus of stargazin, which facilitates the cell membrane localization of SR and inhibits its activity. AMPA receptor activation internalizes SR and disrupts its interaction with stargazin, therefore de-repressing SR's activity, leading to more D-serine production and potentially facilitating NMDA receptor activation. These interactions regulate the enzymatic activity as well as the intracellular localization of SR, potentially coupling the activities of NMDA and AMPA receptors. This shuttling of a neurotransmitter synthesizing enzyme between two receptors appears to be a novel mode of synaptic regulation.
    The Journal of biological chemistry. 08/2014;
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    ABSTRACT: NMDA receptor (NMDAR) hypofunction is a compelling hypothesis for the pathophysiology of schizophrenia, because in part, NMDAR antagonists cause symptoms in healthy adult subjects that resemble schizophrenia. Therefore, NMDAR antagonists have been used as a method to induce NMDAR hypofunction in animals as a pharmacological model of schizophrenia. Serine racemase-null mutant (SR-/-) mice display constitutive NMDAR hypofunction due to the lack of d-serine. SR-/- mice have deficits in tropomyosin-related kinase receptor (TrkB)/Akt signaling and activity regulated cytoskeletal protein (Arc) expression, which mirror what is observed in schizophrenia. Thus, we analyzed these signaling pathways in MK801 sub-chronically (0.15mg/kg; 5days) treated adult wild-type mice. We found that in contrast to SR-/- mice, the activated states of downstream signaling molecules, but not TrkB, increased in MK801 treated mice. Furthermore, there is an age-dependent change in the behavioral reaction of people to NMDAR antagonists. We therefore administered the same dosing regimen of MK801 to juvenile mice and compared them to juvenile SR-/- mice. Our findings demonstrate that pharmacological NMDAR antagonism has different effects on TrkB/Akt signaling than genetically-induced NMDAR hypofunction. Given the phenotypic disparity between the MK801 model and schizophrenia, our results suggest that SR-/- mice more accurately reflect NMDAR hypofunction in schizophrenia. Copyright © 2014. Published by Elsevier B.V.
    Schizophrenia Research 01/2015; · 4.43 Impact Factor

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