Since their discovery in the mammalian CNS, d-aspartate and d-serine have aroused a strong interest with regard to their role as putative neuromodulatory molecules. Whereas the functional role of d-serine as an endogenous coagonist of NMDA receptors (NMDARs) has been elucidated, the biological significance of d-aspartate in the brain is still mostly unclear. In the present study, we demonstrated that nonphysiological high levels of d-aspartate (1) increased in vivo NMDAR activity, (2) attenuated prepulse inhibition deficits induced by amphetamine and MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine hydrogen maleate], (3) produced striatal adaptations of glutamate synapses resembling those observed after chronic haloperidol treatment, and (4) enhanced hippocampal NMDAR-dependent memory. This evidence was obtained using two different experimental strategies that produced an abnormal increase of endogenous d-aspartate levels in the mouse: a genetic approach based on the targeted deletion of the d-aspartate oxidase gene and a pharmacological approach based on oral administration of d-aspartate. This work provides in vivo evidence of a neuromodulatory role exerted by d-aspartate on NMDAR signaling and raises the intriguing hypothesis that also this d-amino acid, like d-serine, could be used as a therapeutic agent in the treatment of schizophrenia-related symptoms.

The authors report that Rhes, a striatal-specific protein, activates mTOR. Rhes-depleted mice showed reduced dyskinesia, but maintained motor improvement following L-DOPA treatment. L-DOPA–induced dyskinesia, the rate-limiting side effect in the therapy of Parkinson's disease, is mediated by activation of mammalian target of rapamycin (mTOR) signaling in the striatum. We found that Ras homolog enriched in striatum (Rhes), a striatal-specific protein, binds to and activates mTOR. Moreover, Rhes−/− mice showed reduced striatal mTOR signaling and diminished dyskinesia, but maintained motor improvement on L-DOPA treatment, suggesting a therapeutic benefit for Rhes-binding drugs.