Editors' ChoiceNeuroscience

New connections: NMDARs in learning and memory

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Science Signaling  18 Jun 2019:
Vol. 12, Issue 586, eaay3846
DOI: 10.1126/scisignal.aay3846

Studies provide critical insight into the roles and regulation of NMDA receptors in learning and memory.

The abundance and activity of N-methyl d-aspartate receptors (NMDARs), glutamate-gated cation channels in neurons, modulate the synaptic plasticity that underlies neuronal development, connectivity, and cognition. As such, mutations in genes encoding NMDAR subunits are associated with a spectrum of neurological disorders. In this week’s issue of Science Signaling, Soto et al. characterize a loss-of-function mutation in the gene encoding GluN2B, which resulted in Rett-like syndrome in a 5-year-old patient. Intriguingly, they show how a simple dietary supplement may effectively overcome NMDAR deficiency in patients. Cultured mouse hippocampal neurons expressing the mutant form of GRIN2B found in the patient showed impaired NMDAR channel activity and dendritic morphology.. However, treating the cells with the NMDAR agonist d-serine reversed these defects. Supplementing the patient’s diet with l-serine, which is a natural stereoisomer and metabolic precursor of d-serine found in various foods, increased the amount of d-serine in the patient’s plasma and cerebrospinal fluid and remarkably improved the patient’s cognitive, social, and motor performance. Also, in this week’s issue, Afonso et al. show that the RNA binding protein heterogenous nuclear ribonucleoprotein K (hnRNP K) is critical for the increased abundance of GluN2B-containing NMDA receptors that occurs in neuronal synapses in response to activity, such as during learning. In cultured rodent hippocampal neurons stimulated with the neurotrophin brain-derived neurotrophic factor (BDNF), hnRNP K stimulated the translation of the mRNA encoding the kinase PYK2 specifically in the synapse, which in turn promoted increased expression of GluN2B and increased synaptic formation and integration of GluN2B-containing NMDARs. These findings pinpoint a critical kinase and an RNA binding protein in the role of synaptic plasticity, which helps define their association with neurological disorders.

In the Archives, Yu et al. found that the acid-sensing channel ASIC1a promoted the synaptic abundance and function of NMDARs in response to changes in extracellular pH. ASIC1a is present in neurons in the striatum. By activating a kinase-dependent transcriptional program that promotes the expression of NMDAR subunits (including GluN2B), ASIC1a channels stimulated synaptic activity and dendritic spine maturation in the striatal neurons that facilitate motor learning. Mice lacking ASIC1a were slower to learn new motor coordination tasks. These findings may have implications for both neuronal development and neuronal disorders that affect the striatum and motor control. Together, these studies provide critical insight into the roles and regulation of NMDARs that further explain the etiology of neurological disorders as well as identify potentially effective therapies or therapeutic targets for patients.

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