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 language | English (US) |
|---|---|
| Pages (from-to) | 681-688 |
| Number of pages | 8 |
| Journal | Cell Reports |
| Volume | 11 |
| Issue number | 5 |
| DOIs | |
| State | Published - 2015 |
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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 journal › Article
}
TY - JOUR
T1 - Selective Role of the Catalytic PI3K Subunit p110β in Impaired Higher Order Cognition in Fragile X Syndrome
AU - Gross, Christina
AU - Raj, Nisha
AU - Molinaro, Gemma
AU - Allen, Amanda G.
AU - Whyte, Alonzo J.
AU - Gibson, Jay R.
AU - Huber, Kimberly M.
AU - Gourley, Shannon L.
AU - Bassell, Gary J.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
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U2 - 10.1016/j.celrep.2015.03.065
DO - 10.1016/j.celrep.2015.03.065
M3 - Article
VL - 11
SP - 681
EP - 688
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 5
ER -