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Suppression of exaggerated NMDAR activity by memantine treatment ameliorates neurological and behavioral deficits in aminopeptidase P1-deficient mice

Cited 4 time in Web of Science Cited 4 time in Scopus
Authors

Bae, Young-Soo; Yoon, Sang Ho; Kim, Young Sook; Oh, Sung Pyo; Song, Woo Seok; Cha, Jin Hee; Kim, Myoung-Hwan

Issue Date
2022-08
Publisher
생화학분자생물학회
Citation
Experimental and Molecular Medicine, Vol.54 No.8, pp.1109-1124
Abstract
Inherited neurodevelopmental disorders: Repairing neural circuitry as a treatment Addressing neurological symptoms may offer new treatments for inborn errors of metabolism (IEMs) affecting neurodevelopment. In such IEMs, mutation of an enzyme disrupts a metabolic pathway, causing buildup or lack of key molecules, with symptoms including hyperactivity, developmental delay, and intellectual disability. Because the detailed pathological mechanisms of most IEMs are unknown, there are no treatments for resulting neurological issues. Myoung-Hwan Kim at Seoul National University and co-workers investigated whether they could treat the neurological symptoms of the IEM, aminopeptidase P1 (APP1) deficiency. They found that APP1 deficiency in mice caused an increase in the neural receptor NMDAR. Suppressing NMDAR reduced both neurological and behavioral symptoms. These findings suggest potential treatments for APP1 deficiency, and indicate that neurodevelopmental disorders in IEMs may be treated by repairing the neural circuitry instead of the root metabolic cause. Inborn errors of metabolism (IEMs) are common causes of neurodevelopmental disorders, including microcephaly, hyperactivity, and intellectual disability. However, the synaptic mechanisms of and pharmacological interventions for the neurological complications of most IEMs are unclear. Here, we report that metabolic dysfunction perturbs neuronal NMDA receptor (NMDAR) homeostasis and that the restoration of NMDAR signaling ameliorates neurodevelopmental and cognitive deficits in IEM model mice that lack aminopeptidase P1. Aminopeptidase P1-deficient (Xpnpep1(-/-)) mice, with a disruption of the proline-specific metalloprotease gene Xpnpep1, exhibit hippocampal neurodegeneration, behavioral hyperactivity, and impaired hippocampus-dependent learning. In this study, we found that GluN1 and GluN2A expression, NMDAR activity, and the NMDAR-dependent long-term potentiation (LTP) of excitatory synaptic transmission were markedly enhanced in the hippocampi of Xpnpep1(-/-) mice. The exaggerated NMDAR activity and NMDAR-dependent LTP were reversed by the NMDAR antagonist memantine. A single administration of memantine reversed hyperactivity in adult Xpnpep1(-/-) mice without improving learning and memory. Furthermore, chronic administration of memantine ameliorated hippocampal neurodegeneration, hyperactivity, and impaired learning and memory in Xpnpep1(-/-) mice. In addition, abnormally enhanced NMDAR-dependent LTP and NMDAR downstream signaling in the hippocampi of Xpnpep1(-/-) mice were reversed by chronic memantine treatment. These results suggest that the metabolic dysfunction caused by aminopeptidase P1 deficiency leads to synaptic dysfunction with excessive NMDAR activity, and the restoration of synaptic function may be a potential therapeutic strategy for the treatment of neurological complications related to IEMs.
ISSN
1226-3613
URI
https://hdl.handle.net/10371/185679
DOI
https://doi.org/10.1038/s12276-022-00818-9
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