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

Authors :
Christina Gross
Nisha Raj
Gemma Molinaro
Amanda G. Allen
Alonzo J. Whyte
Jay R. Gibson
Kimberly M. Huber
Shannon L. Gourley
Gary J. Bassell
Source :
Cell Reports, Vol 11, Iss 5, Pp 681-688 (2015)
Publication Year :
2015
Publisher :
Elsevier, 2015.

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.

Subjects

Subjects :
Biology (General)
QH301-705.5

Details

Language :
English
ISSN :
22111247
Volume :
11
Issue :
5
Database :
Directory of Open Access Journals
Journal :
Cell Reports
Publication Type :
Academic Journal
Accession number :
edsdoj.503f1f74b54f07ba444d74a3b4f8e2
Document Type :
article
Full Text :
https://doi.org/10.1016/j.celrep.2015.03.065