Activity‐induced secretion of semaphorin 3A mediates learning

Jitsuki-Takahashi, Aoi; Jitsuki, Susumu; Yamashita, Naoya; Kawamura, Minoru; Abe, Manabu; Sakimura, Kenji; Sano, Akane; Nakamura, Fumio; Goshima, Yoshio

doi:10.1111/ejn.15210

Cited by 16 publications

(12 citation statements)

References 49 publications

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“…Semaphorins have important functions in neurodevelopment, including guiding axonal growth, dendritic arborization, and regulating synaptic formation 65 . Activity‐induced secretion of SEMA3A was found to mediate contextual memory formation by increasing AMPA (α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid) receptor expression in hippocampal synapses via the NRP‐1–PLXNA4–SEMA3A complex 66 . Together, our pathway analyses suggest that reduced VEC expression in AD brains is potentially associated with cognitive impairment through reduced SEMA3A ‐mediated hippocampal learning.…”

Section: Resultsmentioning

confidence: 99%

Vascular endothelial‐cadherin as a marker of endothelial injury in preclinical Alzheimer disease

Tarawneh

Kasper

Sanford

et al. 2022

Ann Clin Transl Neurol

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Objective Endothelial dysfunction is an early and prevalent pathology in Alzheimer disease (AD). We here investigate the value of vascular endothelial‐cadherin (VEC) as a cerebrospinal fluid (CSF) marker of endothelial injury in preclinical AD. Methods Cognitively normal participants (Clinical Dementia Rating [CDR] 0) from the Knight Washington University‐ADRC were included in this study (n = 700). Preclinical Alzheimer's Cognitive Composite (PACC) scores, CSF VEC, tau, p‐tau181, Aβ42/Aβ40, neurofilament light‐chain (NFL) levels, and magnetic resonance imaging (MRI) assessments of white matter injury (WMI) were obtained from all participants. A subset of participants underwent brain amyloid imaging using positron emission tomography (amyloid‐PET) (n = 534). Linear regression examined associations of CSF VEC with PACC and individual cognitive scores in preclinical AD. Mediation analyses examined whether CSF VEC mediated effects of CSF amyloid and tau markers on cognition in preclinical AD. Results CSF VEC levels significantly correlated with PACC and individual cognitive scores in participants with amyloid (A+T±N±; n = 558) or those with amyloid and tau pathologies (A+T+N±; n = 259), after adjusting for covariates. CSF VEC also correlated with CSF measures of amyloid, tau, and neurodegeneration and global amyloid burden on amyloid‐PET scans in our cohort. Importantly, our findings suggest that CSF VEC mediates associations of CSF Aβ42/Aβ40, p‐tau181, and global amyloid burden with cognitive outcomes in preclinical AD. Interpretation Our results support the utility of CSF VEC as a marker of endothelial injury in AD and highlight the importance of endothelial injury as an early pathology that contributes to cognitive impairment in even the earliest preclinical stages.

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Section: Resultsmentioning

confidence: 99%

Vascular endothelial‐cadherin as a marker of endothelial injury in preclinical Alzheimer disease

Tarawneh

Kasper

Sanford

et al. 2022

Ann Clin Transl Neurol

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“…Besides the established function for the semaphorins and their receptors (Nrp and plexin family members) in neurodevelopment (32,58), only a few lines of evidence demonstrated their involvement in homeostatic and Hebbian forms of plasticity in the adult hippocampus (31,50,59,60). Notably, Nrp1 is localised at synapses of the adult rat hippocampus (60) and secreted semaphorins acting on the sema-Nrp-plexin complex modulate synaptic connectivity in granule cells of dentate gyrus and pyramidal neurons of CA1 (60) as well as AMPA receptor trafficking in CA3-CA1 synapses (50). The present study adds to this body of literature by demonstrating that Nrp1 is required for the formation of hippocampal long-term memory.…”

Section: Discussionmentioning

confidence: 99%

“…Upon the confirmation with two independent shRNA sequences, we focused on Nrp1 which has been shown to be regulated by enriched environment exposure(57) and within dentate gyrus memory engrams(48). Besides the established function for the semaphorins and their receptors (Nrp and plexin family members) in neurodevelopment(32,58), only a few lines of evidence demonstrated their involvement in homeostatic and Hebbian forms of plasticity in the adult hippocampus(31,50,59,60). Notably, Nrp1 is localised at synapses of the adult rat hippocampus(60) and secreted semaphorins acting on the sema-Nrp-plexin complex modulate synaptic connectivity in granule cells of dentate gyrus and pyramidal neurons of CA1(60) as well as AMPA receptor trafficking in CA3-CA1 synapses(50).…”

Section: Discussionmentioning

confidence: 99%

“…Nrp1 is known to build a complex with Semaphorin 3a (Sema3A) and Plexin A4 and is implicated in signalling pathways regulating neuronal morphology (31,49). Although it has been demonstrated that this complex is important for AMPA receptor trafficking (50), is still unknown whether Nrp1 plays a role in hippocampus-dependent memory formation. We performed a shRNA-mediated loss-offunction approach to assess the role of Nrp1 in memory formation.…”

Section: Neuropilin-1 Is a Dnmt3a1 Downstream Target Required For Mem...mentioning

confidence: 99%

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Dnmt3a1 regulates hippocampus-dependent memory via the downstream target Nrp1

Kupke

Klimmt

Mudlaff

et al. 2023

Preprint

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Epigenetic factors are well established players in memory formation. Specifically, DNA methylation is necessary for the formation of long-term memory in multiple brain regions including the hippocampus. Despite the demonstrated role for DNA methyltransferases (Dnmts) in memory formation, it is unclear whether individual Dnmts have unique or redundant functions in long-term memory formation. Furthermore, the downstream processes controlled by Dnmts during memory consolidation have not been investigated. In this study, we examined the requirement of the predominant Dnmt in the adult brain, Dnmt3a1, for hippocampus-dependent long-term memory formation. Using RNA-sequencing, we identified an activity-regulated Dnmt3a1-dependent genomic program in which several genes were functionally associated with functional and structural plasticity. Our data showed that Dnmt3a1, similarly to its isoform Dnmt3a2, plays a critical role in memory formation and identified Neuropilin 1 (Nrp1) as a downstream target of Dnmt3a1 in this process. Intriguingly, we found that Nrp1 expression is selectively regulated by and a specific downstream effector of Dnmt3a1, but not Dnmt3a2. Taken together, our study uncovered a Dnmt3a-isoform-specific mechanism in memory formation, identified a novel regulator of memory, and further highlighted the complex and highly regulated functions of distinct epigenetic regulators in brain function.

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“…Interestingly, each Sema3 molecule differentially and precisely regulates various cognitive function through its speci c receptor complex. A recent study reported that Sema3A-plexinA4 signaling mediated fear learning and memory through decreased phosphorylation of serine 522 of CRMP2 [75]. Future studies are needed to delineate how Sema3A in uences CRMP2-mediated cognitive dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Ozone Decreases CRMP2 Phosphorylation by Inhibiting Sema3A to Ameliorate Chronic REM Sleep Deprivation-Induced Cognitive Deficits in Mice

jingru

Williams

Sun

et al. 2022

Preprint

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Sleep is essential for proper cognitive functioning. Ozone can delay both the aging process as well as the associated neurodegeneration. An untested hypothesis is that ozone may play a role in reducing the cognitive impairment associated with sleep deprivation. This study was designed to elucidate the mechanism of ozone’s effect on chronic REM sleep deprivation induced cognitive dysfunction in mice. Ozone ameliorated cognitive dysfunction in chronic REM sleep deprived mice, increased the number of dendritic spines in the hippocampus region and decreased neuronal loss. Administration of ozone may protect against chronic REM sleep deprivation induced cognitive dysfunction by enhancing the expression of Semaphorin 3A (Sema3A) and PlexinA1 concentrations as well as P-CRMP2/CRMP2 in the hippocampus. Moreover, ozone was associated with acetylation of α-tubulin which, in turn, is associated with microtubule network dynamics and modulates ATP synthase activity. In conclusion, ozone may play a neuroprotective role and improve chronic REM sleep deprivation induced spatial recognition and learning memory dysfunction in mice.

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Activity‐induced secretion of semaphorin 3A mediates learning

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 16 publications

References 49 publications

Vascular endothelial‐cadherin as a marker of endothelial injury in preclinical Alzheimer disease

Vascular endothelial‐cadherin as a marker of endothelial injury in preclinical Alzheimer disease

Dnmt3a1 regulates hippocampus-dependent memory via the downstream target Nrp1

Ozone Decreases CRMP2 Phosphorylation by Inhibiting Sema3A to Ameliorate Chronic REM Sleep Deprivation-Induced Cognitive Deficits in Mice

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