Increased expression of the PI3K enhancer PIKE mediates deficits in synaptic plasticity and behavior in fragile X syndrome.
The PI3K enhancer PIKE links PI3K catalytic subunits to group 1 metabotropic glutamate receptors (mGlu1/5) and activates PI3K signaling. The roles of PIKE in synaptic plasticity and the etiology of mental disorders are unknown. Here, we show that increased PIKE expression is a key mediator of impaired mGlu1/5-dependent neuronal plasticity in mouse and fly models of the inherited intellectual disability fragile X syndrome (FXS). Normalizing elevated PIKE protein levels in FXS mice reversed deficits in molecular and cellular plasticity and improved behavior. Notably, PIKE reduction rescued PI3K-dependent and -independent neuronal defects in FXS. We further show that PI3K signaling is increased in a fly model of FXS and that genetic reduction of the Drosophila ortholog of PIKE, CenG1A rescued excessive PI3K signaling, mushroom body defects, and impaired short-term memory in these flies. Our results demonstrate a crucial role of increased PIKE expression in exaggerated mGlu1/5 signaling causing neuronal defects in FXS.
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: christina.gross@cchmc.org.
Christina
C
Gross
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Chia-Wei
CW
Chang
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Seth M
SM
Kelly
Center for Neural Science, New York University, New York, NY 10003, USA.
Aditi
A
Bhattacharya
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Sean M J
SM
McBride
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Scott W
SW
Danielson
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Michael Q
MQ
Jiang
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Chi Bun
CB
Chan
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Keqiang
K
Ye
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Jay R
JR
Gibson
Center for Neural Science, New York University, New York, NY 10003, USA.
Eric
E
Klann
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Thomas A
TA
Jongens
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Kenneth H
KH
Moberg
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Kimberly M
KM
Huber
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 / Q000502:physiology*; D001921:Brain / Q000378:metabolism; D049229:Dendritic Spines / Q000378:metabolism; D004195:Disease Models, Animal; D004330:Drosophila / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000378:metabolism / Q000473:pathology*; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D024521:Mushroom Bodies / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009473:Neuronal Plasticity; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D014176:Protein Biosynthesis; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D015398:Signal Transduction
D029721:Drosophila Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D020558:GTP Phosphohydrolases; D020690:GTPase-Activating Proteins; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C497684:Fmr1 protein, mouse; C000598893:centaurin gamma1A, Drosophila; C104077:metabotropic glutamate receptor type 1; C529781:PIKE protein, mouse