Selective Role of the Catalytic PI3K Subunit p110β in Impaired Higher Order Cognition in Fragile X Syndrome
Distinct isoforms of the PI3K catalytic subunit have specialized functions in the brain, but their role in cognition is unknown. Here, we show that the catalytic subunit p110β plays an important role in prefrontal cortex (PFC)-dependent cognitive defects in mouse models of Fragile X syndrome (FXS),...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2015-05-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124715003563 |
| _version_ | 1819015346654281728 |
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| author | Christina Gross Nisha Raj Gemma Molinaro Amanda G. Allen Alonzo J. Whyte Jay R. Gibson Kimberly M. Huber Shannon L. Gourley Gary J. Bassell |
| author_facet | Christina Gross Nisha Raj Gemma Molinaro Amanda G. Allen Alonzo J. Whyte Jay R. Gibson Kimberly M. Huber Shannon L. Gourley Gary J. Bassell |
| author_sort | Christina Gross |
| collection | DOAJ |
| description | Distinct isoforms of the PI3K catalytic subunit have specialized functions in the brain, but their role in cognition is unknown. Here, we show that the catalytic subunit p110β plays an important role in prefrontal cortex (PFC)-dependent cognitive defects in mouse models of Fragile X syndrome (FXS), an inherited intellectual disability. FXS is caused by loss of function of the fragile X mental retardation protein (FMRP), which binds and translationally represses mRNAs. PFC-selective knockdown of p110β, an FMRP target that is translationally upregulated in FXS, reverses deficits in higher cognition in Fmr1 knockout mice. Genetic full-body reduction of p110β in Fmr1 knockout mice normalizes excessive PI3K activity, restores stimulus-induced protein synthesis, and corrects increased dendritic spine density and behavior. Notably, adult-onset PFC-selective Fmr1 knockdown mice show impaired cognition, which is rescued by simultaneous p110β knockdown. Our results suggest that FMRP-mediated control of p110β is crucial for neuronal protein synthesis and cognition. |
| first_indexed | 2024-12-21T02:30:17Z |
| format | Article |
| id | doaj.art-ae503f1f74b54f07ba444d74a3b4f8e2 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-21T02:30:17Z |
| publishDate | 2015-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-ae503f1f74b54f07ba444d74a3b4f8e22022-12-21T19:18:57ZengElsevierCell Reports2211-12472015-05-0111568168810.1016/j.celrep.2015.03.065Selective Role of the Catalytic PI3K Subunit p110β in Impaired Higher Order Cognition in Fragile X SyndromeChristina Gross0Nisha Raj1Gemma Molinaro2Amanda G. Allen3Alonzo J. Whyte4Jay R. Gibson5Kimberly M. Huber6Shannon L. Gourley7Gary J. Bassell8Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USADepartment of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USADepartment of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USADepartment of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USADepartment of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USADepartment of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USADepartment of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USADepartment of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USADepartment of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USADistinct isoforms of the PI3K catalytic subunit have specialized functions in the brain, but their role in cognition is unknown. Here, we show that the catalytic subunit p110β plays an important role in prefrontal cortex (PFC)-dependent cognitive defects in mouse models of Fragile X syndrome (FXS), an inherited intellectual disability. FXS is caused by loss of function of the fragile X mental retardation protein (FMRP), which binds and translationally represses mRNAs. PFC-selective knockdown of p110β, an FMRP target that is translationally upregulated in FXS, reverses deficits in higher cognition in Fmr1 knockout mice. Genetic full-body reduction of p110β in Fmr1 knockout mice normalizes excessive PI3K activity, restores stimulus-induced protein synthesis, and corrects increased dendritic spine density and behavior. Notably, adult-onset PFC-selective Fmr1 knockdown mice show impaired cognition, which is rescued by simultaneous p110β knockdown. Our results suggest that FMRP-mediated control of p110β is crucial for neuronal protein synthesis and cognition.http://www.sciencedirect.com/science/article/pii/S2211124715003563 |
| spellingShingle | Christina Gross Nisha Raj Gemma Molinaro Amanda G. Allen Alonzo J. Whyte Jay R. Gibson Kimberly M. Huber Shannon L. Gourley Gary J. Bassell Selective Role of the Catalytic PI3K Subunit p110β in Impaired Higher Order Cognition in Fragile X Syndrome Cell Reports |
| title | Selective Role of the Catalytic PI3K Subunit p110β in Impaired Higher Order Cognition in Fragile X Syndrome |
| title_full | Selective Role of the Catalytic PI3K Subunit p110β in Impaired Higher Order Cognition in Fragile X Syndrome |
| title_fullStr | Selective Role of the Catalytic PI3K Subunit p110β in Impaired Higher Order Cognition in Fragile X Syndrome |
| title_full_unstemmed | Selective Role of the Catalytic PI3K Subunit p110β in Impaired Higher Order Cognition in Fragile X Syndrome |
| title_short | Selective Role of the Catalytic PI3K Subunit p110β in Impaired Higher Order Cognition in Fragile X Syndrome |
| title_sort | selective role of the catalytic pi3k subunit p110β in impaired higher order cognition in fragile x syndrome |
| url | http://www.sciencedirect.com/science/article/pii/S2211124715003563 |
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