The neural circuit mechanisms underlying neurological complications in most IEMs are currently unknown.

To date, more than 1000 distinct IEMs have been identified 5, and the most serious and common outcomes in IEMs are neurodevelopmental disorders, such as developmental delay, microcephaly, hyperactivity, attention deficit, autism, and intellectual disability 6, 7, 8, 9, 10, 11. Although an individual IEM is rare (incidence < 1:100,000) owing largely to a recessive inheritance pattern, IEMs are collectively common disorders with an incidence of 1:800–2500 births and account for more than 15% of single-gene disorders 2, 3, 4. Inborn errors of metabolism (IEMs), also known as inheritable metabolic diseases, are caused mainly by mutations in a single gene that encodes an enzyme in a specific metabolic pathway 1.

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. In addition, abnormally enhanced NMDAR-dependent LTP and NMDAR downstream signaling in the hippocampi of Xpnpep1 –/– mice were reversed by chronic memantine treatment. Furthermore, chronic administration of memantine ameliorated hippocampal neurodegeneration, hyperactivity, and impaired learning and memory in Xpnpep1 –/– mice. A single administration of memantine reversed hyperactivity in adult Xpnpep1 –/– mice without improving learning and memory. The exaggerated NMDAR activity and NMDAR-dependent LTP were reversed by the NMDAR antagonist memantine. 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. 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. 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. However, the synaptic mechanisms of and pharmacological interventions for the neurological complications of most IEMs are unclear. Inborn errors of metabolism (IEMs) are common causes of neurodevelopmental disorders, including microcephaly, hyperactivity, and intellectual disability.

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