Developmental Inhibition of Gsk3 Rescues Behavioral and Neurophysiological Deficits in a Mouse Model of Schizophrenia Predisposition
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While the genetic basis of schizophrenia is increasingly well characterized, novel treatments will require establishing mechanistic relationships between specific risk genes and core phenotypes. Rare, highly penetrant risk genes such as the 22q11.2 microdeletion are promising in this regard. Df(16)A(+/-) mice, which carry a homologous microdeletion, have deficits in hippocampal-prefrontal connectivity that correlate with deficits in spatial working memory. These mice also have deficits in axonal development that are accompanied by dysregulated Gsk3β signaling and can be rescued by Gsk3 antagonists. Here we show that developmental inhibition of Gsk3 rescues deficits in hippocampal-prefrontal connectivity, task-related neural activity, and spatial working memory behavior in Df(16)A(+/-) mice. Taken together, these results provide mechanistic insight into how the microdeletion results in cognitive deficits, and they suggest possible targets for novel therapies.
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Inhibition of Gsk3β signaling in juvenile Df(16)A +/- mice rescues the functional connectivity between the hippocampus and prefrontal cortex and improves working memory in these mice.
“Consistent with this hypothesis, inhibition of Gsk3 β signaling in juvenile Df(16)A +/-mice rescues the functional connectivity between the hippocampus and prefrontal cortex and improves working memory in these mice 79 .”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [79]
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References 68 · Cited by 98
- Authors
- Tamura, M., Mukai, J., Gordon, J. A., & Gogos, J. A.
- Affiliations
- Tanabe Pharma Corporation (Japan) (JP)
- Columbia University (US)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Gordon, Joshua A.
- Gogos, Joseph A.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 89
- Issue
- 5
- Pages
- 1100-1109
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC4783174
- OpenAlex
- W2281931174
- Cited by
- 98
- References
- 68
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 5 · 2023: 4 · 2022: 11 · 2021: 9 · 2020: 9 · 2019: 10 · 2018: 16 · 2017: 18 · 2016: 5
- FWCI
- 14.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01mh096274-06)
- National Institute of Mental Health (R01-MH096274)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- schizophrenia, 22q11.2 microdeletion, GSK3β signaling, spatial working memory, axonal development, neuronal activity, cognitive impairment, risk genes, mouse model
- MeSH terms
- Action Potentials, Analysis of Variance, Animals, Animals, Newborn, Mental Disorders, Cognition Disorders, DiGeorge Syndrome, Disease Models, Animal, Evoked Potentials, Mice, Inbred C57BL, Mice, Transgenic, Nervous System Diseases, Schizophrenia, Theta Rhythm, Maze Learning, Genetic Predisposition to Disease, Glycogen Synthase Kinase 3, Mice
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