D-serine is a co-agonist of NMDA receptor (NMDAR) and plays important roles in synaptic plasticity mechanisms. Serine racemase (SR) is a brain-enriched enzyme that converts L-serine to D-serine. SR interacts with the protein interacting with C-kinase 1 (PICK1), which is known to direct protein kinase C (PKC) to its targets in cells. Here, we investigated whether PKC activity regulates SR activity and D-serine availability in the brain. In vitro, PKC phosphorylated SR and decreased its activity. PKC activation increased SR phosphorylation in serine residues and reduced D-serine levels in astrocyte and neuronal cultures. Conversely, PKC inhibition decreased basal SR phosphorylation and increased cellular D-serine levels. In vivo modulation of PKC activity regulated both SR phosphorylation and D-serine levels in rat frontal cortex. Finally, rats that completed an object recognition task showed decreased SR phosphorylation and increased D-serine/total serine ratios, which was markedly correlated with decreased PKC activity in both cortex and hippocampus. Results indicate that PKC phosphorylates SR in serine residues and regulates D-serine availability in the brain. This interaction may be relevant for the regulation of physiological and pathological mechanisms linked to NMDAR function.
Changes in D-serine availability in the brain may contribute to the hypofunction of NMDA-glutamate receptors in schizophrenia; however, measurements of blood levels of D-serine in individuals with schizophrenia have not been consistent amongst previous studies. Here we studied plasma levels of D-serine and L-serine in 84 Brazilian individuals with schizophrenia and 75 gender- and age-matched controls. Plasma levels of D-serine and the ratio of plasma D-serine to total serine were significantly lower in individuals with schizophrenia as compared to the control group. Levels of D-serine were significantly and negatively correlated to the severity of negative symptoms of schizophrenia. We also observed that plasma levels of D-serine significantly decreased with aging in healthy controls. Our results suggest that the possible role of D-serine in the pathophysiology of schizophrenia should be further investigated, with possible implications for the drug treatment of this disorder.
Assembly of synapses requires proper coordination between pre- and postsynaptic elements. Identification of cellular and molecular events in synapse formation and maintenance is a key step to understand human perception, learning, memory, and cognition. A key role for astrocytes in synapse formation and function has been proposed. Here, we show that transforming growth factor ? (TGF-?) signaling is a novel synaptogenic pathway for cortical neurons induced by murine and human astrocytes. By combining gain and loss of function approaches, we show that TGF-?1 induces the formation of functional synapses in mice. Further, TGF-?1-induced synaptogenesis involves neuronal activity and secretion of the co-agonist of the NMDA receptor, D-serine. Manipulation of D-serine signaling, by either genetic or pharmacological inhibition, prevented the TGF-?1 synaptogenic effect. Our data show a novel molecular mechanism that might impact synaptic function and emphasize the evolutionary aspect of the synaptogenic property of astrocytes, thus shedding light on new potential therapeutic targets for synaptic deficit diseases.
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