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Cited by 178Schizophrenia research and treatmentAxon Guidance and Neuronal SignalingGenetics and Neurodevelopmental Disorders

Molecular Substrates of Altered Axonal Growth and Brain Connectivity in a Mouse Model of Schizophrenia

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Mukai, Jun, Tamura, Makoto, Fénelon, Karine, Rosen, Andrew M., Spellman, Timothy J., Kang, Rujun, MacDermott, Amy B., Karayiorgou, Maria +2 more·2015·Neuron
DOI 10.1016/j.neuron.2015.04.003PMC PMC4603834
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Abstract

22q11.2 deletion carriers show specific cognitive deficits, and ∼30% of them develop schizophrenia. One of the disrupted genes is ZDHHC8, which encodes for a palmitoyltransferase. We show that Zdhhc8-deficient mice have reduced palmitoylation of proteins that regulate axonal growth and branching. Analysis of axonal projections of pyramidal neurons from both Zdhhc8-deficient and Df(16)A(+/-) mice, which model the 22q11.2 deletion, revealed deficits in axonal growth and terminal arborization, which can be prevented by reintroduction of active ZDHHC8 protein. Impaired terminal arborization is accompanied by a reduction in the strength of synaptic connections and altered functional connectivity and working memory. The effect of ZDHHC8 is mediated in part via Cdc42-dependent modulation of Akt/Gsk3β signaling at the tip of the axon and can be reversed by pharmacologically decreasing Gsk3β activity during postnatal brain development. Our findings provide valuable mechanistic insights into the cognitive and psychiatric symptoms associated with a schizophrenia-predisposing mutation.

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  • Deficits in callosal axonal development and arborization compromise synaptic transmission of adult mice in a 22q11.2 deletion model.

    “Mukai and colleagues, using a mouse model with 22q11.2 deletion, specifically designed for studying SCZ, found that deficits in callosal axonal development and arborization compromise synaptic transmission of adult mice108”

    From CYFIP1 governs the development of cortical axons by modulating calcium availability (2025) · cites this paper as [108]

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Authors
Mukai, J., Tamura, M., Fénelon, K., Rosen, A. M., Spellman, T. J., Kang, R., MacDermott, A. B., Karayiorgou, M., Gordon, J. A., & Gogos, J. A.
Affiliations
  • Columbia University (US)
  • Tanabe Pharma Corporation (Japan) (JP)
  • New York State Psychiatric Institute (US)
  • University of British Columbia (CA)
Corresponding author
Gogos, Joseph A.
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2015-05
Volume
86
Issue
3
Pages
680-695
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2015.04.003
PMC
PMC4603834
OpenAlex
W1994677962
Cited by
178
References
4
Citations by year
2026: 11 · 2025: 17 · 2024: 10 · 2023: 20 · 2022: 19 · 2021: 13 · 2020: 13 · 2019: 13 · 2018: 23 · 2017: 19 · 2016: 14 · 2015: 5
FWCI
16.52
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5r01mh096274-06)
  • National Institute of Mental Health (R01-MH096274, T32MH018870, R01MH067068, MH 67068, R01MH097879)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
schizophrenia, 22q11.2 deletion syndrome, palmitoylation, axon growth, axon branching, terminal arborization, pyramidal neurons, synaptic efficacy, brain functional connectivity, working memory, Cdc42, Akt/GSK-3β signaling, postnatal brain development, mouse model
MeSH terms
Channelrhodopsins, Acyltransferases, Age Factors, Alzheimer Disease, Animals, Animals, Newborn, Axons, Brain, DiGeorge Syndrome, Disease Models, Animal, Embryo, Mammalian, Humans, Membrane Proteins, Mice, Transgenic, Neural Pathways, Neurons, Phosphopyruvate Hydratase, Signal Transduction, Synapsins, Gene Expression Regulation, Developmental, Excitatory Postsynaptic Potentials, Green Fluorescent Proteins, Mice

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