Altered hippocampal gene expression, glial cell population, and neuronal excitability in aminopeptidase P1 deficiency

Yoon, Sang Ho; Bae, Young Soo; Oh, Sung Pyo; Song, Woo Seok; Chang, Hojin; Kim, Myoung-Hwan

doi:10.1038/s41598-020-79656-6

Cited by 3 publications

(2 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar to RalBP1 −/− mice that exhibit reduced p-eEF2/eEF2 ratio [ 4 ], the hippocampal p-eEF2 levels were significantly reduced in Xpnpep1 −/− mice (Fig. 1 m), which exhibit epileptic electroencephalogram rhythms and abnormally enhanced excitability of hippocampal CA3 pyramidal neurons [ 13 , 14 ], indicating the eEF2 phosphorylation status is sensitive to basal neural activity.…”

Section: Main Textmentioning

confidence: 96%

The phosphorylation status of eukaryotic elongation factor-2 indicates neural activity in the brain

Yoon

Song

et al. 2021

Mol Brain

Self Cite

View full text Add to dashboard Cite

Assessment of neural activity in the specific brain area is critical for understanding the circuit mechanisms underlying altered brain function and behaviors. A number of immediate early genes (IEGs) that are rapidly transcribed in neuronal cells in response to synaptic activity have been used as markers for neuronal activity. However, protein detection of IEGs requires translation, and the amount of newly synthesized gene product is usually insufficient to detect using western blotting, limiting their utility in western blot analysis of brain tissues for comparison of basal activity between control and genetically modified animals. Here, we show that the phosphorylation status of eukaryotic elongation factor-2 (eEF2) rapidly changes in response to synaptic and neural activities. Intraperitoneal injections of the GABA A receptor (GABAAR) antagonist picrotoxin and the glycine receptor antagonist brucine rapidly dephosphorylated eEF2. Conversely, potentiation of GABAARs or inhibition of AMPA receptors (AMPARs) induced rapid phosphorylation of eEF2 in both the hippocampus and forebrain of mice. Chemogenetic suppression of hippocampal principal neuron activity promoted eEF2 phosphorylation. Novel context exploration and acute restraint stress rapidly modified the phosphorylation status of hippocampal eEF2. Furthermore, the hippocampal eEF2 phosphorylation levels under basal conditions were reduced in mice exhibiting epilepsy and abnormally enhanced excitability in CA3 pyramidal neurons. Collectively, the results indicated that eEF2 phosphorylation status is sensitive to neural activity and the ratio of phosphorylated eEF2 to total eEF2 could be a molecular signature for estimating neural activity in a specific brain area.

show abstract

Section: Main Textmentioning

confidence: 96%

The phosphorylation status of eukaryotic elongation factor-2 indicates neural activity in the brain

Yoon

Song

et al. 2021

Mol Brain

Self Cite

View full text Add to dashboard Cite

show abstract

“…The common alterations of neurodegeneration and different factors associated with the metabolic syndrome are present in ALS [ 75 ]. Deficiencies of certain types of aminopeptidases cause brain atrophy, loss of neurons in the retina and brain, neurodegeneration of the hippocampus, and impaired learning and memory [ 76 , 77 , 78 ]. In addition, pharmacological modulation of aminopeptidases could help reduce central hypertension and reduced glutamate excitability [ 79 ].…”

Section: Resultsmentioning

confidence: 99%

Systematic Review and Meta-Analyses of Aminopeptidases as Prognostic Biomarkers in Amyotrophic Lateral Sclerosis

Teruel-Peña

Gómez‐Urquiza

Suleiman‐Martos

et al. 2023

IJMS

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons in the spinal cord, brain stem, and cerebral cortex. Biomarkers for ALS are essential for disease detection and to provide information on potential therapeutic targets. Aminopeptidases catalyze the cleavage of amino acids from the amino terminus of protein or substrates such as neuropeptides. Since certain aminopeptidases are known to increase the risk of neurodegeneration, such mechanisms may reveal new targets to determine their association with ALS risk and their interest as a diagnostic biomarker. The authors performed a systematic review and meta-analyses of genome-wide association studies (GWASs) to identify reported aminopeptidases genetic loci associated with the risk of ALS. PubMed, Scopus, CINAHL, ISI Web of Science, ProQuest, LILACS, and Cochrane databases were searched to retrieve eligible studies in English or Spanish, published up to 27 January 2023. A total of 16 studies were included in this systematic review, where a series of aminopeptidases could be related to ALS and could be promising biomarkers (DPP1, DPP2, DPP4, LeuAP, pGluAP, and PSA/NPEPPS). The literature reported the association of single-nucleotide polymorphisms (SNPs: rs10260404 and rs17174381) with the risk of ALS. The genetic variation rs10260404 in the DPP6 gene was identified to be highly associated with ALS susceptibility, but meta-analyses of genotypes in five studies in a matched cohort of different ancestry (1873 cases and 1861 control subjects) showed no ALS risk association. Meta-analyses of eight studies for minor allele frequency (MAF) also found no ALS association for the “C” allele. The systematic review identified aminopeptidases as possible biomarkers. However, the meta-analyses for rs1060404 of DPP6 do not show a risk associated with ALS.

show abstract

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

et al. 2022

View full text Add to dashboard Cite

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.

show abstract

Altered hippocampal gene expression, glial cell population, and neuronal excitability in aminopeptidase P1 deficiency

Cited by 3 publications

References 60 publications

The phosphorylation status of eukaryotic elongation factor-2 indicates neural activity in the brain

The phosphorylation status of eukaryotic elongation factor-2 indicates neural activity in the brain

Systematic Review and Meta-Analyses of Aminopeptidases as Prognostic Biomarkers in Amyotrophic Lateral Sclerosis

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

Contact Info

Product

Resources

About