Selective Role of the Catalytic PI3K Subunit p110β in Impaired Higher Order Cognition in Fragile X Syndrome

Christina Gross, Nisha Raj, Gemma Molinaro, Amanda G. Allen, Alonzo J. Whyte, Jay R. Gibson, Kimberly M. Huber, Shannon L. Gourley, Gary J. Bassell

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)681-688
Number of pages8
JournalCell Reports
Volume11
Issue number5
DOIs
StatePublished - 2015

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Fragile X Mental Retardation Protein
Fragile X Syndrome
Phosphatidylinositol 3-Kinases
Cognition
Catalytic Domain
Prefrontal Cortex
Knockout Mice
Dendritic Spines
Brain
Protein Isoforms
Proteins
Intellectual Disability
Messenger RNA
Defects

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Selective Role of the Catalytic PI3K Subunit p110β in Impaired Higher Order Cognition in Fragile X Syndrome. / Gross, Christina; Raj, Nisha; Molinaro, Gemma; Allen, Amanda G.; Whyte, Alonzo J.; Gibson, Jay R.; Huber, Kimberly M.; Gourley, Shannon L.; Bassell, Gary J.

In: Cell Reports, Vol. 11, No. 5, 2015, p. 681-688.

Research output: Contribution to journalArticle

Gross, Christina ; Raj, Nisha ; Molinaro, Gemma ; Allen, Amanda G. ; Whyte, Alonzo J. ; Gibson, Jay R. ; Huber, Kimberly M. ; Gourley, Shannon L. ; Bassell, Gary J. / Selective Role of the Catalytic PI3K Subunit p110β in Impaired Higher Order Cognition in Fragile X Syndrome. In: Cell Reports. 2015 ; Vol. 11, No. 5. pp. 681-688.
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