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), 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.
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: christina.gross@cchmc.org.
Christina
C
Gross
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Nisha
N
Raj
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Gemma
G
Molinaro
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA; Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322, USA.
Amanda G
AG
Allen
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA; Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322, USA.
Alonzo J
AJ
Whyte
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Jay R
JR
Gibson
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Kimberly M
KM
Huber
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA; Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322, USA.
Shannon L
SL
Gourley
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: gbassel@emory.edu.
Gary J
GJ
Bassell
D000818:Animals; D001522:Behavior, Animal; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000737:chemistry / Q000378:metabolism*; D003071:Cognition / Q000502:physiology*; D049229:Dendritic Spines / Q000378:metabolism; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017397:Prefrontal Cortex / Q000378:metabolism; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism
D058543:Class Ia Phosphatidylinositol 3-Kinase; D051860:Fragile X Messenger Ribonucleoprotein 1; D064529:Receptor, Metabotropic Glutamate 5; C497684:Fmr1 protein, mouse