25 June 2013. D-serine, a simple compound that boosts glutamate signals, might reinvigorate the effort to treat schizophrenia by this pathway, according to a report published May 31 in Proceedings of the National Academy of Sciences. Led by Joseph Coyle of Harvard Medical School in Boston, Massachusetts, the study supports the idea that underactive glutamate signaling generates the brain disturbances characteristic of the disorder, and argues that these may be fixed in adulthood. One line of glutamate drug development came to an end last year when Eli Lilly and Company abandoned its metabotropic glutamate receptor compound (see SRF related news story), so this study may inject some hope into this area.
The study expands upon the group’s previous work with mice designed to have underachieving glutamate systems, achieved by giving them sluggish N-methyl-D-aspartate (NMDA) receptors. Activating NMDA receptors requires not only glutamate, but also a cofactor, one of which is D-serine. But these mice lack serine racemase, an enzyme that makes D-serine, which lowers their D-serine levels and results in underactive NMDA receptors and cognitive deficits (Basu et al., 2009). The new study further probes the consequences of going without D-serine in the brain and turns up a series of anomalies that already have links to schizophrenia.
First author Darrick Balu and colleagues focused on the dentate granule cells of the hippocampus, a region long suspected in schizophrenia. There they found decreased signals flowing through NMDA receptors of dentate granule neurons in the serine racemase mice compared to controls. They found less plasticity there, too, as measured by long-term potentiation (LTP), which depends on NMDA receptor activation. Similar to what has been found in postmortem brains in schizophrenia, the dentate granule neurons in the mutant mice exhibited sparser dendritic spines and reduced expression of spine-promoting molecules miR-132 and brain-derived nerve growth factor (BDNF) compared to controls. The researchers also found diminished signaling downstream of NMDA receptor activation in the Akt/mTOR pathway, which may also contribute to dendrite outgrowth (and is linked to schizophrenia suspect molecules such as DISC1 [see SRF related news story] and the dopamine D2 receptor [see SRF related news story]). The pattern of anomalies there suggested a damaged mechanism for protein synthesis.
This list of perturbations could be remedied in adulthood by adding back D-serine, the researchers found. Injecting the adult mice under the skin for 20 days not only restored hippocampal D-serine levels to normal, but also rescued the deficits in LTP, BDNF expression, and Akt/mTOR signaling. The researchers do not report whether there were changes in dendrite structure, however. Moving to behavior, the researchers found that these mice had impaired fear conditioning when treated with saline but not when treated with D-serine: serine racemase knockouts receiving D-serine remembered as well as wild-type mice that a certain sound or place predicted an electric shock.
The study provides convergent evidence supporting the glutamate hypothesis of schizophrenia (see SRF Hypothesis and SRF Webinar). But maybe more interestingly, it suggests that a longstanding deficit in NMDA receptor function may be remedied in adulthood, similar to recent findings about neuregulin (see SRF related news story). If the human brain retains sufficient plasticity in adulthood, this may bode well for clinical trials of D-serine currently underway (see SRF related news story).—Michele Solis.
Balu DT, Li Y, Puhl MD, Benneyworth MA, Basu AC, Takagi S, Bolshakov VY, Coyle JT. Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction. Proc Natl Acad Sci U S A. 2013 May 31. Abstract