Increased Expression of the PI3K Enhancer PIKE Mediates Deficits in Synaptic Plasticity and Behavior in Fragile X Syndrome
Open accessAbstract
The PI3K enhancer PIKE links PI3K catalytic subunits to group 1 metabotropic glutamate receptors (mGlu1/5) and activates PI3K signaling. The roles of PIKE in synaptic plasticity and the etiology of mental disorders are unknown. Here, we show that increased PIKE expression is a key mediator of impaired mGlu1/5-dependent neuronal plasticity in mouse and fly models of the inherited intellectual disability fragile X syndrome (FXS). Normalizing elevated PIKE protein levels in FXS mice reversed deficits in molecular and cellular plasticity and improved behavior. Notably, PIKE reduction rescued PI3K-dependent and -independent neuronal defects in FXS. We further show that PI3K signaling is increased in a fly model of FXS and that genetic reduction of the Drosophila ortholog of PIKE, CenG1A rescued excessive PI3K signaling, mushroom body defects, and impaired short-term memory in these flies. Our results demonstrate a crucial role of increased PIKE expression in exaggerated mGlu1/5 signaling causing neuronal defects in FXS.
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Core FXS mouse deficits, including protein synthesis, dendritic spine density and morphology, long-term depression, and audiogenic seizures, are consistently rescued by more than ten genetic approaches and multiple drug classes.
“One striking conclusion of the broad array of preclinical studies is that these core deficits can be consistently rescued by more than ten genetic approaches and multiple classes of pharmacological compounds including mGluR antagonists (MPEP, fenobam, mavoglurant and CTEP), GABA agonists, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), mechanistic target of rapamycin (mTOR) inhib”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [54]
Mutations in Fmr1 and Pten lead to over-activity of the PI3K/AKT pathway with increased synaptogenesis and hyperconnectivity of neurons.
“while mutations in Fmr1 and Pten lead to the over-activity of PI3K/AKT pathway with increased synaptogenesis and hyperconnectivity of the neurons [107–109]”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [108]
Downregulation of the PI3K/AKT pathway in Fmr1 null mice ameliorated aberrations in protein synthesis, dendritic spine density and cortical network connectivity.
“while downregulation of the pathway in Fmr1 null mice ameliorated aberrations in protein synthesis, dendritic spine density and cortical network connectivity [108, 109].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [108]
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References 43 · Cited by 117
- Authors
- Gross, C., Chang, C.-W., Kelly, S. M., Bhattacharya, A., McBride, S. M. J., Danielson, S. W., Jiang, M. Q., Chan, C. B., Ye, K., Gibson, J. R., Klann, E., Jongens, T. A., Moberg, K. H., Huber, K. M., & Bassell, G. J.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- The University of Texas Southwestern Medical Center (US)
- Emory University (US)
- New York University (US)
- University of Pennsylvania (US)
- Corresponding author
- Gross, Christina
- Bassell, Gary J.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2015-05
- Volume
- 11
- Issue
- 5
- Pages
- 727-736
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4418204
- OpenAlex
- W2130431667
- Cited by
- 117
- References
- 43
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 6 · 2023: 5 · 2022: 12 · 2021: 8 · 2020: 16 · 2019: 15 · 2018: 12 · 2017: 15 · 2016: 13 · 2015: 8
- FWCI
- 10.93
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion, cc-by-nc-nd)
- Funders
- U.S. Department of Defense (AR1101189)
- Autism Speaks
- FRAXA Research Foundation (AR1101189)
- Charles H. Revson Foundation
- University of Pennsylvania
- Emory University (P30NS055077)
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health (N S04738 4, N S03400 7)
- National Institute of Mental Health (R25MH060490, R21MH105353, MH105353)
- National Institute of Neurological Disorders and Stroke (R37NS034007, NS-047384, R01NS034007, R01NS045711, R29NS034007, P30NS055077, NS-034007, NS045711, R01NS047384)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD056370, R01HD056370)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
- Keywords
- pike, fragile X syndrome, PI3K signaling, metabotropic glutamate receptors, synaptic plasticity, intellectual disability, short-term memory, mushroom body, Drosophila, neuroplasticity
- MeSH terms
- Animals, Behavior, Animal, Brain, Disease Models, Animal, Drosophila, Fragile X Syndrome, Gene Expression Regulation, Nerve Tissue Proteins, Neuronal Plasticity, Protein Biosynthesis, Signal Transduction, Receptors, Metabotropic Glutamate, Mice, Knockout, Phosphatidylinositol 3-Kinases, GTP Phosphohydrolases, GTPase-Activating Proteins, Mushroom Bodies, Drosophila Proteins, Dendritic Spines, Mice, Fragile X Messenger Ribonucleoprotein 1, Receptor, Metabotropic Glutamate 5
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