NMDA receptors (NMDARs) participate in processes ranging from neural development to learning and memory. Disorders of NMDAR signaling are linked to several neurological diseases. Accumulating evidence suggests that the endogenous co-agonist D-serine plays a prominent role in activation of synaptic NMDARs in cortex. However, there are significant gaps in our understanding of the physiological mechanisms involved in D-serine homeostasis in brain and their potential impact on NMDAR signaling. Our preliminary data suggest that SLC1A4, a neutral amino acid transporter paralog within the SLC1 solute carrier family that includes glutamate transporters, unexpectedly mediates transmembrane flux of D-serine. We will test the hypotheses that SLC1A4 is in fact the major route of sodium-dependent D-serine uptake in brain and that selective SLC1A4 inhibitors developed from a hydroxyproline pharmacophore can alter D-serine homeostasis and thereby modulate NMDAR function and synaptic plasticity. We will also characterize the structure and function of a recently identified mutation in the human gene encoding SLC1A4 that is linked to neurodevelopmental and cognitive deficits, and we will create and study a transgenic mouse model of this human disease.
NMDA receptors play key roles in learning and memory as well as brain development. Disrupted NMDA receptor signaling has been associated with a number of neurological disorders. This project is focused on D-Serine, an amino acid that together with glutamate activates NMDA receptors in the brain. We propose to determine the mechanisms that regulate the brain's levels of D-serine, which are important in controlling receptor signaling. We will test the theory that an amino acid transporter known as SLC1A4 plays a previously unrecognized role in reuptake of D-serine. We have developed new inhibitors of SLC1A4 that we hypothesize can modulate D-serine levels in brain, an approach that may hold promise for treating brain disorders including schizophrenia and cognitive impairment.
