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J. Clin. Invest., May 08 2025, e184299 | https://doi.org/10.1172/JCI184299
GluN2B suppression restores phenylalanine-induced neuroplasticity and cognition impairments in a mouse model of phenylketonuria
Woo Seok Song1,2, Young Sook Kim1,2, Young-Soo Bae1, Sang Ho Yoon1,2,4, Jae Min Lim1, and Myoung-Hwan Kim1,2,3,5
1Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Korea.
2Neuroscience Research Institute, Seoul National University Medical Research Center, Seoul, 03080, Korea.
3Seoul National University Bundang Hospital, Seongnam, Gyeonggi, 13620, Korea.
4Present address: Department of Anatomy & Neurobiology, University of California Irvine, Irvine, CA, 92697, USA.
5Corresponding author: Myoung-Hwan Kim
1Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Korea.
2Neuroscience Research Institute, Seoul National University Medical Research Center, Seoul, 03080, Korea.
3Seoul National University Bundang Hospital, Seongnam, Gyeonggi, 13620, Korea.
4Present address: Department of Anatomy & Neurobiology, University of California Irvine, Irvine, CA, 92697, USA.
5Corresponding author: Myoung-Hwan Kim
Abstract
Phenylketonuria (PKU), an inborn error of phenylalanine (Phe) metabolism, is a common cause of intellectual disability. However, the mechanisms by which elevated phenylalanine (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 NMDARs in hippocampal CA1 neurons. L-Phe-induced hyperactivation of extrasynaptic GluN2B resulted in 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 with GluN2B inhibitors. Furthermore, pharmacological and virus-mediated suppression of GluN2B reversed the impaired learning in PahEnu2 mice. Collectively, these results suggest that 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.
논문정보
- Research article
- 2025년 05월 (BRIC 등록일 2025-05-13)
- 국내 연구진
- 의약학 > 신경의학
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