D-Serine and NMDA Receptors
The NMDA (N-methyl-D-aspartate) receptor (also known as NMDAR), is a glutamate receptor and ion channel protein found in nerve cells. It is activated when glutamate and glycine (or D-serine) bind to it, and when activated it allows positively charged ions to flow through the cell membrane.
D-Serine supplementation can reduce symptoms of cognitive decline. It is also able to reduce symptoms of diseases characterized by reduced NMDA signaling, which includes cocaine dependence and schizophrenia.
Treatment with D-serine can improve performance in tasks related to recognition learning and working memory, suggesting that this agent can be useful for the treatment of disorders involving declines in these cognitive domains. 
Because a structural abnormality and NMDA receptor hypofunction has been demonstrated in the cortex and hippocampus of schizophrenic subjects, D-serine treatment may offer a new therapeutic approach to diseases related to the hypofunction of NMDA receptors such as schizophrenia.
Define: hypofunction: Reduced, low, or inadequate function.
D-Serine, synthesized in the brain by serine racemase from L-serine (its enantiomer), serves as a neuromodulator by coactivating NMDA receptors, making them able to open if they then also bind glutamate. D-serine is a potent agonist at the glycine site of the NMDA-type glutamate receptor (NMDAR). For the receptor to open, glutamate and either glycine or D-serine must bind to it; in addition a pore blocker must not be bound (e.g. Mg2+ or Pb2+). In fact, D-serine is a more potent agonist at the glycine site on the NMDAR than glycine itself.
Define: agonist: (biochemistry) A molecule that can combine with a receptor on a cell to produce a physiological reaction.
D-Serine is an obligatory endogenous coagonist of the NMDA receptor, functioning in vivo as a specific and potent full agonist at the NMDAR-associated glycine modulatory site.
Define: endogenous: (biology) growing or originating from within an organism.
Define: co-agonist: (biochemistry) A drug or other chemical that can combine with a receptor on a cell to produce a physiologic reaction typical of a naturally occurring substance. Co-agonist implies it is one of other agonists working in conjunction.
In addition to alleviating several diseases and conditions, D-serine may have its dark side in neurodegenerative disease. D-serine may play a role in excitotoxic neuronal death in Alzheimer’s disease and also in amyotrophic lateral sclerosis (ALS) as a principal cause for motoneuron death (considered to be excitotoxicity). The presence of endogenous D-serine has been shown to be necessary for most, if not all, NMDAR-mediated excitotoxicity observed in rat brain slices and in vivo. Pretreatment of rat hippocampal organotypic slices with D-serine deaminase was shown to practically abolish NMDA-mediated excitotoxicity, suggesting that D-serine, rather than glycine, participates in these excitotoxic events in the hippocampus.
It is conceivable that D-serine signalling could be involved in brain disorders in which NMDARs contributes to the pathophysiology, such as stroke. Here, an indirect reduction of NMDAR-mediated excitotoxicity through modified D-serine supply may in principle suggest new therapeutic avenues. It is encouraging in that respect that SR deletion (i.e. serine racemase (SR), which converts L-serine to D-serine) was recently reported to reduce tissue damage in a mouse stroke model (Mustafa et al., 2010). However, increasing D-serine levels might on the other hand help to overcome cognitive impairments related to the dysfunction of NMDAR signaling. Promising early studies showed that Dcycloserine, a partial agonist at the NMDAR co-agonist site, can improve spatial learning in rats (Monahan et al., 1989). Therapeutic approaches targeting D-serine signaling will therefore have to strike the balance between preventing NMDAR-dependent damage and avoiding cognitive impairment.
Define: excitotoxicity: Excitotoxicity is the pathological process by which nerve cells are damaged or killed by excessive stimulation by neurotransmitters such as glutamate and similar substances.
- Schizophrenia, symptoms - https://www.sane.org/mental-health-and-illness/facts-and-guides/schizophrenia
- OCD, Glycine - https://www.hindawi.com/archive/2014/859735/
- Oxidative Stress
- Oxidation & it's results - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964749/#R37
- Increasing D-serine levels may help to overcome cognitive impairments related to the dysfunction of NMDAR signaling.
- Increasing D-serine levels may cause NMDAR-dependent damage.
- D-serine treatment may offer a new therapeutic approach to diseases related to the hypofunction of NMDA receptors such as schizophrenia.
- NMDA Receptor, Wikipedia, https://en.wikipedia.org/wiki/NMDA_receptor
- D-Serine', Examine, https://examine.com/supplements/d-serine/
- Effects of low-dose D-serine on recognition and working memory in mice,https://www.ncbi.nlm.nih.gov/pubmed/21556803
- Effect of systemic administration of D-serine on the levels of D- and L-serine in several brain areas and periphery of rat,https://www.ncbi.nlm.nih.gov/pubmed/15249164
- Farlex Partner Medical Dictionary,© Farlex 2012
- D-Serine in Neuropsychiatric Disorders: New Advances,Hindawi,https://www.hindawi.com/archive/2014/859735/
- Define: endogenous,Google,https://www.google.com/search?q=define%3Aendogenous
- D-serine as a gliotransmitter and its roles in brain development and disease,https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3632749/
- D-Serine: A key to synaptic plasticity?,https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3375648/pdf/ukmss-48553.pdf