PAKs inhibitors ameliorate schizophrenia-associated dendritic spine deterioration in vitro and in vivo during late adolescence
Open accessAbstract
Significance: Drug discovery in psychiatry has been limited to chemical modifications of compounds originally discovered serendipitously. Therefore, more mechanism-oriented strategies of drug discovery for mental disorders are awaited. Schizophrenia is a devastating mental disorder with synaptic disconnectivity involved in its pathophysiology. In this study, we studied a biological pathway underlying synaptic disturbance and examined whether p21-activated kinase inhibitors ameliorate the pathology in vitro and in vivo. The beneficial effects of these inhibitors reported here may provide us with an opportunity for drug discovery in major mental illnesses with synaptic disturbance.
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Loss of DISC1 leads to constituent activation of Rac1 signaling and spine loss via p21-activated kinase (PAK) signaling.
“Loss of DISC1 leads to constituent activation of Rac1 signaling and spine loss via p21-activated kinase (PAK) signaling131,132 (Fig. 4, orange).”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [132]
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Stress weakens prefrontal networks: molecular insults to higher cognition
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Altering the course of schizophrenia: progress and perspectives
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- Authors
- Hayashi-Takagi, A., Araki, Y., Nakamura, M., Vollrath, B., Duron, S. G., Yan, Z., Kasai, H., Huganir, R. L., Campbell, D. A., & Sawa, A.
- Affiliations
- Departments of aPsychiatry and
- Johns Hopkins University (US)
- Center for Disease Biology and Integrative Medicine, The University of Tokyo (JP)
- Afraxis (United States) (US)
- Afraxis, Inc., San Diego, CA 92121; and
- University at Buffalo, State University of New York (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-04-03
- Volume
- 111
- Issue
- 17
- Pages
- 6461-6466
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4035976
- OpenAlex
- W1981225314
- Cited by
- 101
- References
- 5
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 7 · 2023: 8 · 2022: 5 · 2021: 7 · 2020: 10 · 2019: 6 · 2018: 10 · 2017: 10 · 2016: 11 · 2015: 16 · 2014: 4
- FWCI
- 10.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Johns Hopkins University
- National Alliance for Research on Schizophrenia and Depression (MH-084018, MH-094268, MH-092443)
- Maryland Stem Cell Research Fund
- Japan Society for the Promotion of Science (084018, 24116003, 26293260, 21000009)
- National Institute of Mental Health (R21MH085226, MH084018, MH085226, RC1MH088753, MH 092443, MH‑088753, P20MH084018, R01MH069853, MH-094268, P50MH094268, MH069853, R01MH092443)
- National Institute on Drug Abuse (R01DA037618)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- schizophrenia, p21-activated kinase, PAK inhibitors, synaptic dysfunction, DISC1, Rac1, Kalirin-7, NMDA receptor, late adolescence, prepulse inhibition, postsynaptic density
- MeSH terms
- Aging, Animals, Behavior, Animal, Disease Models, Animal, Nerve Tissue Proteins, Neuronal Plasticity, Pyridones, Pyrimidines, Schizophrenia, Synapses, Receptors, N-Methyl-D-Aspartate, Prefrontal Cortex, RNA Interference, Protein Kinase Inhibitors, Dendritic Spines, Mice, Rats, p21-Activated Kinases, Gene Knockdown Techniques
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