D-Serine and Glycine Differentially Control Neurotransmission during Visual Cortex Critical Period

Abstract

N-methyl-D-aspartate receptors (NMDARs) play a central role in synaptic plasticity. Their activation requires the binding of both glutamate and d-serine or glycine as co-agonist. The prevalence of either co-agonist on NMDA-receptor function differs between brain regions and remains undetermined in the visual cortex (VC) at the critical period of postnatal development. Here, we therefore investigated the regulatory role that d-serine and/or glycine may exert on NMDARs function and on synaptic plasticity in the rat VC layer 5 pyramidal neurons of young rats. Using selective enzymatic depletion of d-serine or glycine, we demonstrate that d-serine and not glycine is the endogenous co-agonist of synaptic NMDARs required for the induction and expression of Long Term Potentiation (LTP) at both excitatory and inhibitory synapses. Glycine on the other hand is not involved in synaptic efficacy per se but regulates excitatory and inhibitory neurotransmission by activating strychnine-sensitive glycine receptors, then producing a shunting inhibition that controls neuronal gain and results in a depression of synaptic inputs at the somatic level after dendritic integration. In conclusion, we describe for the first time that in the VC both D-serine and glycine differentially regulate somatic depolarization through the activation of distinct synaptic and extrasynaptic receptors.

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“…Furthermore, they demonstrated that there was a close correspondence in the expression of SR, NMDAR, especially glutamate, glycine, and PCP binding sites, and D‐serine levels in the forebrain and an inverse association in DAAO expression and D‐serine levels in the cerebellum and hindbrain where glycine was found in high concentrations . Thus, they concluded that D‐serine is the primary co‐agonist at synaptic NMDAR in the forebrain . They succeeded in the purification and characterization of SR from the rat brain in 1999 .…”

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“…The actual real specificity of these compounds remains unknown and could display unwanted off-target effects as illustrated for OHAsp, PES and PM, which have been largely used to inhibit SR [42][43][44][45][46][47][48] Therefore, the specificity of a putative inhibitor has to be first validated in SR −/− or DAAO −/− mice, depending on the target of the compound. The actual real specificity of these compounds remains unknown and could display unwanted off-target effects as illustrated for OHAsp, PES and PM, which have been largely used to inhibit SR [42][43][44][45][46][47][48] Therefore, the specificity of a putative inhibitor has to be first validated in SR −/− or DAAO −/− mice, depending on the target of the compound.…”

“…Thus, it has been reported that OHAsp introduced in the astrocytes impaired LTP recorded in hippocampal slices although no rundown in glutamatergic responses was observed 42 or reduced NMDA-excitatory postsynaptic currents (EPSCs)-EPSCs recorded at layer 5 pyramidal neurons, 44 effects that could be fully rescued by adding D-serine back to tissues. 47 Application of PES and PMS to neonatal mouse cerebellum slices impedes neuronal migration 48 and also decreases respiratory frequency when applied to brainstem slices. Using bath application, PES was found to reduce light-evoked NMDAR response in the retina, 46 or the EPSCs and LTP in the visual cortex.…”

“…A second source of false positives comes from the use of pharmacological tools to inhibit SR or DAAO. The actual real specificity of these compounds remains unknown and could display unwanted off-target effects as illustrated for OHAsp, PES and PM, which have been largely used to inhibit SR [42][43][44][45][46][47][48] Therefore, the specificity of a putative inhibitor has to be first validated in SR −/− or DAAO −/− mice, depending on the target of the compound.…”

“…Using bath application, PES was found to reduce light-evoked NMDAR response in the retina, 46 or the EPSCs and LTP in the visual cortex. 47 Application of PES and PMS to neonatal mouse cerebellum slices impedes neuronal migration 48 and also decreases respiratory frequency when applied to brainstem slices. 43 In all these studies, the inhibitory effects of the compounds were counteracted by application of D-serine and were opposed to the enzymatic degradation of D-serine by applied DAAO, just apparently warranting the use of the SR inhibitors.…”