Targeted disruption of serine racemase affects glutamatergic neurotransmission and behavior

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.

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).

Department of Psychiatry, Harvard Medical School, Belmont, MA, USA

A C Basu, L Han, M A Benneyworth, M P Froimowitz, N Lange & J T Coyle

Laboratory for Psychiatric and Molecular Neuroscience, McLean Hospital, Belmont, MA, USA

Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD, USA

Neurostatistics Laboratory, McLean Hospital, Belmont, MA, USA

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