Targeted disruption of serine racemase affects glutamatergic neurotransmission and behavior

A. C. Basu; G. E. Tsai; C. L. Ma; J. T. Ehmsen; A. K. Mustafa; L. Han; Z. I. Jiang; M. A. Benneyworth; M. P. Froimowitz; N. Lange; S. H. Snyder; R. Bergeron; J. T. Coyle

doi:10.1038/mp.2008.130

Targeted disruption of serine racemase affects glutamatergic neurotransmission and behavior

A. C. Basu, G. E. Tsai, C. L. Ma, J. T. Ehmsen, A. K. Mustafa, L. Han, Z. I. Jiang, M. A. Benneyworth, M. P. Froimowitz, N. Lange, S. H. Snyder, R. Bergeron, J. T. Coyle

Research output: Contribution to journal › Article › peer-review

270 Scopus citations

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.

Original language	English (US)
Pages (from-to)	719-727
Number of pages	9
Journal	Molecular psychiatry
Volume	14
Issue number	7
DOIs	https://doi.org/10.1038/mp.2008.130
State	Published - Jul 2009
Externally published	Yes

Bibliographical note

Funding Information:
We thank William Carlezon, Jonathan Picker and Uwe Rudolph for helpful discussions and the use of equipment. We thank Joanne Berger-Sweeney, Paul Ardayfio, Amy Lawson-Yuen and Kiersten Smith for helpful discussions, Julia Dewald and Julie Kurek for assistance in behavioral experiments, and Jiamin Feng for animal colony maintenance and genotyping. We thank Hermann Wolosker for anti-SR antibody. This work was supported by the United States National Institutes of Health under grant numbers 2 P50 MH06045-07A1 (JTC), MH051290 (JTC), MH18501 (SHS), and NS37483 (NL), research scientist award DA00074 (SHS) and training grant number 5T32 AG00222-14 (ACB), by a NARSAD Senior Investigator Award (JTC), and by the Canadian Institutes on Health Research (CIHR) under grant number MPO-79360 (RB) and a new investigator award (RB).

Keywords

D-serine
Glutamate
NMDA receptor
Schizophrenia

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10.1038/mp.2008.130

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title = "Targeted disruption of serine racemase affects glutamatergic neurotransmission and behavior",

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.",

keywords = "D-serine, Glutamate, NMDA receptor, Schizophrenia",

author = "Basu, {A. C.} and Tsai, {G. E.} and Ma, {C. L.} and Ehmsen, {J. T.} and Mustafa, {A. K.} and L. Han and Jiang, {Z. I.} and Benneyworth, {M. A.} and Froimowitz, {M. P.} and N. Lange and Snyder, {S. H.} and R. Bergeron and Coyle, {J. T.}",

note = "Funding Information: We thank William Carlezon, Jonathan Picker and Uwe Rudolph for helpful discussions and the use of equipment. We thank Joanne Berger-Sweeney, Paul Ardayfio, Amy Lawson-Yuen and Kiersten Smith for helpful discussions, Julia Dewald and Julie Kurek for assistance in behavioral experiments, and Jiamin Feng for animal colony maintenance and genotyping. We thank Hermann Wolosker for anti-SR antibody. This work was supported by the United States National Institutes of Health under grant numbers 2 P50 MH06045-07A1 (JTC), MH051290 (JTC), MH18501 (SHS), and NS37483 (NL), research scientist award DA00074 (SHS) and training grant number 5T32 AG00222-14 (ACB), by a NARSAD Senior Investigator Award (JTC), and by the Canadian Institutes on Health Research (CIHR) under grant number MPO-79360 (RB) and a new investigator award (RB).",

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AU - Tsai, G. E.

AU - Ma, C. L.

AU - Ehmsen, J. T.

AU - Mustafa, A. K.

AU - Han, L.

AU - Jiang, Z. I.

AU - Benneyworth, M. A.

AU - Froimowitz, M. P.

AU - Lange, N.

AU - Snyder, S. H.

AU - Bergeron, R.

AU - Coyle, J. T.

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Targeted disruption of serine racemase affects glutamatergic neurotransmission and behavior

Abstract

Bibliographical note

Keywords

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