Telencephalon‐specific <i>Alkbh1</i> conditional knockout mice display hippocampal atrophy and impaired learning

Kawarada, Layla; Fukaya, Masahiro; Saito, Ryo; Kassai, Hidetoshi; Sakagami, Hiroyuki; Aiba, Atsu

doi:10.1002/1873-3468.14098

Cited by 5 publications

(5 citation statements)

References 42 publications

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“…2 C). Finally, Alkbh1 − /− mice were reported to have decreased contextual memory in the contextual and cued fear-conditioning test ( 16 ), but we did not observe any differences in either contextual memory or cued memory in the Albkh8 −/− mice (Fig. S2 ).…”

Section: Resultsmentioning

confidence: 53%

“…Moreover, ELP2 mutations have been detected in patients with ID and autism spectrum disorder ( 39 , 40 ). Behavioral abnormalities indicating loss of learning ability have been observed In Alkbh1 −/− mice ( 16 ). However, the tests used to detect these abnormalities differed from those used for Albkh8 −/− mice in this study (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…However, there have been very few studies on the functions of the ALKBH family in the central nervous system and any possible associations with neurological disorders. ALKBH1 is reported to contribute to axon regeneration ( 15 ) and hippocampus-dependent learning ( 16 ). Alkbh5 deficiency in mice results in profound and deleterious effects on cerebellar development under hypoxic conditions ( 17 ).…”

Section: Introductionmentioning

confidence: 99%

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ALKBH8 contributes to neurological function through oxidative stress regulation

Honda,

Hase,

Tanikawa

et al. 2024

PNAS Nexus

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Transfer RNA (tRNA) modification is essential for proper protein translation, as these modifications play important roles in several biological functions and disease pathophysiologies. AlkB homolog 8 (ALKBH8) is one of the nine mammalian ALKBH family molecules known to regulate selenoprotein translation through the modification of the wobble uridine (U34) in tRNA; however, its specific biological roles remain unclear. In this study, we investigated the role of ALKBH8 using Alkbh8-knockout (Albkh8−/−) mice, which were observed to have reduced 5-methoxycarbonylmethyluridine (mcm5U) and (S)-5-methoxycarbonylhydroxymethyluridine levels; notably, the mcm5U level was partially compensated only in the brain. The results of the novel object recognition test showed reduction in time to explore a novel object in Albkh8−/− mice; increased latency to fall in the rotarod performance test and latency to the immobility period in the forced swim test were also observed. These abnormal behaviors indicate dysfunction of the central nervous system. Furthermore, we observed reduced brain weight and ischemic pathological changes in the cerebral cortex and hippocampus in the form of weak eosin staining in the fiber tracts adjacent to the hippocampal cornu ammonis 1 region and an increase in pyramidal cells in the temporal lobe. Concordantly, we identified the differential expression of oxidative stress-related proteins and metabolites in the cerebral cortex and hippocampus using omics analyses. Finally, neurons and glial cells derived from Albkh8−/− mice show reduced mitochondrial membrane potential. Collectively, these findings indicate that ALKBH8 maintains neural function through an oxidative stress-regulatory mechanism.

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Section: Resultsmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ALKBH8 contributes to neurological function through oxidative stress regulation

Honda,

Hase,

Tanikawa

et al. 2024

PNAS Nexus

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“…In contrast, downregulated genes in the S‐shTeT3 group were significantly enriched in items related to synapse structure and synapse function (purple) compared to the S‐CTR group, whereas upregulated genes were significantly enriched in items related to immune function (red) (Figure 4E ). Moreover, the DEGs in the S‐ShTet3 group compared to the shTet3 group were mainly enriched in respiratory chain complex, oxidoreductase complex, mitochondrial respiratory chain complex, NADH dehydrogenase complex, and Wnt‐activated receptor activity (Figure S4 ), which are antioxidative and may promote cell survival [ 41 ]. Even though there was no difference in synaptic plasticity‐related genes and immune‐related genes between the S‐shTet3 mice and shTet3 mice in NAc, antioxidative stress‐related genes were increased in S‐shTet3 mice compared to shTet3 mice.…”

Section: Resultsmentioning

confidence: 99%

Deficiency of Tet3 in nucleus accumbens enhances fear generalization and anxiety‐like behaviors in mice

et al. 2022

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Stress-induced neuroepigenetic programming gains growing more and more interest in the studies of the etiology of posttraumatic stress disorder (PTSD). However, seldom attention is focused on DNA demethylation in fear memory generalization, which is the core characteristic of PTSD. Here, we show that ten-eleven translocation protein 3 (TET3), the most abundant DNA demethylation enzyme of the TET family in neurons, senses environmental stress and bridges neuroplasticity with behavioral adaptation during fear generalization. Foot shock strength dependently induces fear generalization and TET3 expression in nucleus accumbens (NAc) in mice. Inhibition of DNA demethylation by infusing demethyltransferase inhibitors or AAV-Tet3-shRNA virus in NAc enhances the fear generalization and anxiety-like behavior. Furthermore, TET3 knockdown impairs the dendritic spine density, PSD length, and thickness of neurons, decreases DNA hydroxymethylation (5hmC), reduces the expression of synaptic plasticity-related genes including Homer1, Cdkn1a, Cdh8, Vamp8, Reln, Bdnf, while surprisingly increases immune-related genes Stat1, B2m, H2-Q7, H2-M2, C3, Cd68 shown by RNA-seq. Notably, knockdown of TET3 in NAc activates microglia and CD39-P2Y12R signaling pathway, and inhibition of CD39 reverses the effects of TET3 knockdown on the fear memory generalization and anxiety. Overexpression of TET3 by Crispr-dSaCas9 virus delivery to activate endogenous Tet3 in NAc increases dendritic spine density of neurons in NAc and reverses fear memory generalization and anxiety-like behavior in mice. These results suggest that TET3 modulates fear generalization and anxiety via regulating synaptic plasticity and CD39 signaling pathway.

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“… 17 , 19 Deletion of the Alkbh1 gene increases DNA 6mA levels and leads to transcriptional silencing or activation in multicellular species. 16 , 23 Because ALKBH1 whole-body knockout mice were embryonic lethal or showed neural development defects and sex-ratio distortion, 24 , 25 , 26 tissue-/cell-specific ALKBH1-knockout/knockdown mice were used and showed the important role of ALKBH1-demethylated DNA 6mA modification in regulating osteogenic differentiation, 27 , 28 myogenesis, 29 hippocampal atrophy, 30 axon regeneration, 31 vascular calcification, 32 and cancer cell growth. 17 However, the role of ALKBH1-mediated DNA 6mA modification in diet-induced hepatic metabolic changes and the underlying molecular basis remains unclear.…”

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confidence: 99%