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Cited by 41Memory and Neural MechanismsAxon Guidance and Neuronal SignalingNeuroscience and Neuropharmacology Research

The impact of Semaphorin 4C/Plexin-B2 signaling on fear memory via remodeling of neuronal and synaptic morphology

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Simonetti, Manuela, Paldy, Eszter, Njoo, Christian, Bali, Kiran Kumar, Worzfeld, Thomas, Pitzer, Claudia, Kuner, Thomas, Offermanns, Stefan +2 more·2021·Molecular Psychiatry
DOI 10.1038/s41380-019-0491-4PMC PMC7985029
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Abstract

Aberrant fear is a cornerstone of several psychiatric disorders. Consequently, there is large interest in elucidation of signaling mechanisms that link extracellular cues to changes in neuronal function and structure in brain pathways that are important in the generation and maintenance of fear memory and its behavioral expression. Members of the Plexin-B family of receptors for class 4 semaphorins play important roles in developmental plasticity of neurons, and their expression persists in some areas of the adult nervous system. Here, we aimed to elucidate the role of Semaphorin 4C (Sema4C) and its cognate receptor, Plexin-B2, in the expression of contextual and cued fear memory, setting a mechanistic focus on structural plasticity and exploration of contributing signaling pathways. We observed that Plexin-B2 and Sema4C are expressed in forebrain areas related to fear memory, such as the anterior cingulate cortex, amygdala and the hippocampus, and their expression is regulated by aversive stimuli that induce fear memory. By generating forebrain-specific Plexin-B2 knockout mice and analyzing fear-related behaviors, we demonstrate that Sema4C-PlexinB2 signaling plays a crucial functional role in the recent and remote recall of fear memory. Detailed neuronal morphological analyses revealed that Sema4C-PlexinB2 signaling largely mediates fear-induced structural plasticity by enhancing dendritic ramifications and modulating synaptic density in the adult hippocampus. Analyses on signaling-related mutant mice showed that these functions are mediated by PlexinB2-dependent RhoA activation. These results deliver important insights into the mechanistic understanding of maladaptive plasticity in fear circuits and have implications for novel therapeutic strategies against fear-related disorders.

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  • Absence of semaphorin 4C prevents the increase in spine number during fear learning.

    “absence of semaphorin 4C (sema4C) prevents the increase in spine number during fear learning [55, 56].”

    From The extracellular matrix and perineuronal nets in memory (2022) · cites this paper as [55]

    The Results section on fear conditioning reports that the increase in CA1 spine density did not occur in mice lacking Plexin-B2, not mice lacking Sema4C (page unavailable). A separate Results section reports that Sema4C increases spine density in cultured hippocampal neurons, but that does not establish that its absence prevents a spine-number increase during fear learning. (LLM, conf=0.88)

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  • Sema4C is increased in the hippocampus and ACC following fear conditioning, and sema4C knockout mice show deficits in conditioned fear memory recall.

    “Sema4C, which also associates with PNNs (see above), is increased in the hippocampus and ACC following fear conditioning, and sema4C knockout mice show deficits in conditioned fear memory recall [55].”

    From The extracellular matrix and perineuronal nets in memory (2022) · cites this paper as [55]

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Authors
Simonetti, M., Paldy, E., Njoo, C., Bali, K. K., Worzfeld, T., Pitzer, C., Kuner, T., Offermanns, S., Mauceri, D., & Kuner, R.
Affiliations
  • Heidelberg University (DE)
  • Philipps University of Marburg (DE)
  • Max Planck Institute for Heart and Lung Research (DE)
Corresponding author
Kuner, Rohini
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2019-08-23
Volume
26
Issue
4
Pages
1376-1398
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-019-0491-4
PMC
PMC7985029
OpenAlex
W2969813460
Cited by
41
References
13
Citations by year
2026: 4 · 2025: 4 · 2024: 9 · 2023: 5 · 2022: 10 · 2021: 6 · 2020: 3
FWCI
2.76
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Deutsche Forschungsgemeinschaft (SFB636, SFB1158)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
Plexin-B2, fear memory, contextual fear, cued fear, structural plasticity, dendritic branching, synaptic density, hippocampus, RhoA signaling, amygdala, anterior cingulate cortex, fear-related disorders, aversive stimuli
MeSH terms
Animals, Fear, Memory, Nerve Tissue Proteins, Neurons, Cell Adhesion Molecules, Semaphorins, Mice

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