Figure 1. Sarcosine acts as an NMDAR co-agonist at the glycine binding site.

A, structures for sarcosine and glycine. B, currents evoked from one neuron by applying 100 μm NMDA with the indicated sarcosine (Sar) concentrations. The spikes in the current traces are an artifact of the drug perfusion system. C, mean peak current evoked by 100 μm NMDA with varying sarcosine concentrations in no DCKA (N= 12) or in 1 μm DCKA (N= 7). Peak currents were normalized to that evoked by 100 μm NMDA + 300 μm sarcosine in no DCKA in the same cell. For each cell studied in the absence of DCKA, the peak current obtained in the absence of sarcosine was subtracted from the peak current obtained with sarcosine. Lines show fits to a logistic equation with an EC₅₀ of 26 μm and an N of 1.8 in no DCKA and an EC₅₀ of 53 μm and an N of 2.1 in 1 μm DCKA. D, currents evoked from one neuron by applying 100 μm NMDA with the indicated glycine (Gly) concentrations. E, mean peak current evoked by 100 μm NMDA in varying glycine concentrations (N= 6). Peak currents were normalized to that evoked with 10 μm glycine in the same cell. Line shows a fit to a logistic equation with an EC₅₀ of 61 nm and an N of 1.7. F, currents evoked from one neuron by applying 100 μm NMDA with the indicated sarcosine and DCKA concentrations. G, mean 100 μm NMDA peak currents in 10 μm DCKA, 30 μm sarcosine, and in 30 μm sarcosine + 10 μm DCKA. Peak currents were normalized to that induced by 100 μm NMDA in the absence of sarcosine and DCKA (N= 5) in the same cell. *P < 0.0001 versus other bars by one-way ANOVA. H, currents evoked from one neuron by applying 100 μm NMDA ± 30 μm sarcosine (top panel), 1 μm NFPS (middle panel), and 100 μm NMDA ± 30 μm sarcosine in 1 μm NFPS (bottom panel). The traces in the bottom panel were obtained after applying 1 μm NFPS for 10 min. I, mean 100 μm NMDA + 30 μm sarcosine peak currents before and after a 10 min treatment with 1 μm NFPS. Peak currents were normalized to that induced by 100 μm NMDA in the absence of sarcosine before NFPS treatment in the same cell (N= 5). Mean peak currents before and after NFPS do not differ (P= 0.08 by paired t test). J, mean 100 μm NMDA + 30 μm sarcosine peak currents in neurons from control cultures (N= 6), cultures treated with 1 μm NFPS for 1 h (N= 9), and astrocyte-free cultures (N= 4). Peak currents were normalized to that evoked by 100 μm NMDA alone. P= 0.50 by one-way ANOVA. K, currents evoked from one neuron by applying 100 μm NMDA in the absence and presence of 30 μm sarcosine. Traces are from a neuron that was not plated on an astrocytic feeder layer.