GluN2B suppression restores phenylalanine-induced neuroplasticity and cognition impairments in a mouse model of phenylketonuria
Woo Seok Song, Young Sook Kim, Young-Soo Bae, Sang Ho Yoon, Jae Min Lim, Myoung-Hwan Kim
Woo Seok Song, Young Sook Kim, Young-Soo Bae, Sang Ho Yoon, Jae Min Lim, Myoung-Hwan Kim
View: Text | PDF
Research Article Metabolism Neuroscience

GluN2B suppression restores phenylalanine-induced neuroplasticity and cognition impairments in a mouse model of phenylketonuria

Abstract

Phenylketonuria (PKU), an inborn error of phenylalanine (Phe) metabolism, is a common cause of intellectual disability. However, the mechanisms by which elevated Phe levels cause cognitive impairment remain unclear. Here, we show that submillimolar Phe perturbs synaptic plasticity through the hyperactivation of GluN2B-containing NMDARs. PahEnu2 PKU model mice exhibited submillimolar and supramillimolar concentrations of Phe in the cerebrospinal fluid (CSF) and serum, respectively. l-Phe produced concentration-dependent bidirectional effects on NMDA-induced currents, without affecting synaptic NMDA receptors (NMDARs) in hippocampal CA1 neurons. l-Phe-induced hyperactivation of extrasynaptic GluN2B resulted in activity-dependent downregulation of AMPA receptors during burst or sustained synaptic activity. Administration of l-Phe in mice decreased neural activity and impaired memory, which were blocked by pretreatment with GluN2B inhibitors. Furthermore, pharmacological and virus-mediated suppression of GluN2B reversed the impaired learning in PahEnu2 mice. Collectively, these results suggest the concentration of Phe in the CSF of patients with PKU perturbs extrasynaptic NMDARs and synaptic plasticity and that suppression of GluN2B may have the potential to improve cognitive function in patients with PKU.

Authors

Woo Seok Song, Young Sook Kim, Young-Soo Bae, Sang Ho Yoon, Jae Min Lim, Myoung-Hwan Kim

×

Figure 5

l-Phe loading impairs learning in mice.

Options: View larger image (or click on image) Download as PowerPoint
l-Phe loading impairs learning in mice. (A) Experimental design (top) a...
(A) Experimental design (top) and activity paths (bottom) of mice in the Y maze. (B) The percentage of spontaneous alternation in the Y maze measured 30 minutes after l-Phe or vehicle injections. (C) Mice received l-Phe or vehicle 30 minutes before training (top). Bottom: activity paths of mice during the test session. The test session was conducted 6 hours after the training session. N, novel arm; F, familiar arm; S, start arm. (D) Mice treated with l-Phe spent significantly less time in the novel arm. (E) Ro and l-Phe were administered 1 hour and 30 minutes before the training session of NOR, respectively. Bottom: activity paths of mice during the test session of NOR. F, familiar object; N, novel object. (F and G) Quantification of the distance moved (F) and time spent exploring the 2 objects (G) during the test session of NOR. (H) Relative preference for the novel object was calculated using a discrimination index. Statistical analysis was performed using 2-way ANOVA with post hoc Tukey’s test (B, D, and F−H). **P < 0.01, ***P < 0.001, and NS, P ≥ 0.05.