Hyperactive GluN2B impairs neuroplasticity and cognition in phenylketonuria

Abstract

AbstractPhenylketonuria (PKU), an inborn error of phenylalanine (Phe) metabolism, is a common cause of intellectual disability. However, the mechanism by which elevated Phe levels causes cognitive impairment remains unclear. Here, we show that submillimolar Phe perturbs synaptic plasticity through the hyperactivation of GluN2B-containing NMDARs. L-Phe exhibited dose-dependent bidirectional effects on NMDA-induced currents, without affecting synaptic NMDARs in hippocampal CA1 neurons. L-Phe-induced hyperactivation of extrasynaptic GluN2B resulted in an activity-dependent downregulation of AMPARs during burst or sustained synaptic activity. Administration of L-Phe in mice decreased neural activity and impaired memory, which were blocked by pretreatment of GluN2B inhibitors. Furthermore, pharmacological and virus-mediated suppression of GluN2B reversed impaired learning in the PahEnu2PKU model. Collectively, these results suggest that the concentration of Phe in the cerebrospinal fluid of patients with PKU perturbs extrasynaptic NMDAR and synaptic plasticity, and that suppression of GluN2B may be a therapeutic strategy for improving cognitive function in patients with PKU.