|Education||BS, Tsinghua University|
|Current Position||Medical School|
Johns Hopkins Hospital
D-serine and serine racemase in the etiology of schizophrenia
The discovery of new neurotransmitters over the years has never failed to amaze us. From the traditional neurotransmitters like acetylcholine to gas neurotransmitters like nitric oxide (NO), to the more recent amino acid examples like D-serine, our lab has a long-standing interest in the discovery and characterization of novel neurotransmitters since its establishment almost 50 years ago.
The one I am working on is a neurotransmitter fairly recently discovered by my lab called D-serine. It is a D-amino acid that has been proved to be an endogenous co-agonist of the NR1 subunit of the NMDA receptor. The NMDA receptor is crucial in long-term potentiation (LTP) and hence memory formation. D-serine and serine racemase (SRR), a pyridoxal 5′-phosphate-dependent enzyme that catalyses the conversion of L-serine to D-serine, have both been implicated in the etiology of schizophrenia. My thesis project is focused on the interaction between SRR and another protein called DISC1. Disrupted-in-Schizophrenia-1 (DISC1), one of the most promising candidate genes for schizophrenia and major mental disorders, was originally identified in a chromosomal translocation breakpoint in a large Scottish family co-segregating with schizophrenia and other psychiatric illnesses. In our preliminary studies, we discovered that the expression of the mutant DISC1 may lead to alterations in the protein level of SRR and hence D-ser level compared to WT controls. This deficiency in D-ser level and hypothetically NMDA receptor activation may partly contribute to the etiology of schizophrenia. We are currently using a mouse model developed by Dr. Mikhail Pletnikov’s lab in the Psychiatry Department that selectively expresses mutant DISC1 in astrocytes to further study our findings in an in vivo setting.
Inositol Hexakisphosphate Kinase-3 Regulates the Morphology and Synapse Formation of Cerebellar Purkinje Cells via Spectrin/Adducin. Fu C, Xu J, Li RJ, Crawford JA, Khan AB, Ma TM, Cha JY, Snowman AM, Pletnikov MV, Snyder SH. J Neurosci. 2015 Aug 5;35(31):11056-67. doi: 10.1523/JNEUROSCI.1069-15.2015.PMID:26245967
D-serine in glia and neurons derives from 3-phosphoglycerate dehydrogenase. Ehmsen JT, Ma TM, Sason H, Rosenberg D, Ogo T, Furuya S, Snyder SH, Wolosker H. J Neurosci. 2013 Jul 24;33(30):12464-9. doi: 10.1523/JNEUROSCI.4914-12.2013. PMID:23884950
Pathogenic disruption of DISC1-serine racemase binding elicits schizophrenia-like behavior via D-serine depletion. Ma TM, Abazyan S, Abazyan B, Nomura J, Yang C, Seshadri S, Sawa A, Snyder SH, Pletnikov MV. Mol Psychiatry. 2013 May;18(5):557-67. doi: 10.1038/mp.2012.97. Epub 2012 Jul 17. PMID:22801410
Serine racemase regulated by binding to stargazin and PSD-95: potential N-methyl-D-aspartate-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (NMDA-AMPA) glutamate neurotransmission cross-talk. Ma TM, Paul BD, Fu C, Hu S, Zhu H, Blackshaw S, Wolosker H, Snyder SH. J Biol Chem. 2014 Oct 24;289(43):29631-41. doi: 10.1074/jbc.M114.571604. Epub 2014 Aug 27.PMID:25164819