Endogenous co-agonists of the NMDA receptor modulate contextual fear in trace conditioning

•Cued fear is not affected in glycine transporter 1 heterozygous or serine racemase knockout mice.•Trace conditioned serine racemase knockout mice exhibit a deficit in contextual fear.•Glycine transporter 1 heterozygous knockout mice exhibit enhanced contextual fear.

We have used mutant mice to probe the roles of the endogenous co-agonists of the NMDA receptor (NMDAR), D-serine and glycine, in fear learning and memory. Serine racemase knockout (SR−/−) mice have less than 15% of wild type forebrain levels of D-serine, whereas glycine transporter 1 heterozygous knockout (GlyT1+/−) mice have elevated synaptic glycine. While cued fear was normal in both delay and trace conditioned mice of both mutant genotypes, contextual fear was affected in trace conditioned subjects: SR−/− mice showed decreased contextual freezing, whereas GlyT1+/− mice showed elevated contextual freezing. These results indicate that endogenous co-agonists of the NMDAR modulate the conditioning of contextual fear responses, particularly in trace conditioning. They further suggest that endogenous glycine can compensate for the D-serine deficiency in cued and contextual fear following delay conditioning.