Spinal Nerve Ligation‐Induced Nociceptive Behavior And NMDA Receptor‐Mediated Synaptic Transmission in The Spinal Dorsal Horn Are Altered in Serine Racemase Knockout Mice

Abstract

High levels of D-serine have been found in the mammalian brain. D-serine co-localizes with the N-methyl-D-aspartate (NMDA) receptors to a high degree and acts as an endogenous modulator of the NMDA receptors. D-serine is synthesized from L-serine by serene racemes (SR). To clarify the contribution of SR to synaptic transmission in the central nervous system (CNS), we generated SR knockout (KO) mice. The content of D-serine in the brain of the SR KO mice was confirmed to be less than 10% of that of the control mice. Spinal nerve ligation-induced nociceptive behavior, which is medicated by NMDA receptors in the spinal superficial dorsal horn (SDH), was enhanced in SR KO mice. In contrast, loose ligation and partial ligation of the sciatic nerve induced mechanical allodynia to the same extent in the SR KO and WT mice. NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) were recorded from neurons in the SDH. The ratio of NMDA/non-NMDA receptor-mediated EPSCs evoked by electrical stimulation was smaller in SR KO mice than in WT mice. The time constant of NMDA receptor-mediated EPSCs was longer in SR KO mice than in WT mice. The charge transfer during NMDA receptor-mediated EPSC was larger in SR KO mice than in WT mice. Real-time RT-PCR analysis indicated that the expression level of the NR2B subunit of NMDA receptors was slightly but distinctly increased in SR KO mice. The present results could provide insight into the involvement of SR in synaptic modification, which underlies the pathophysiology of central nervous diseases, including neuropathic nociception. SR KO mice may provide a unique tool for investigating the synaptic action of D-serine in the CNS.