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PI3K signaling in the locus coeruleus: a new molecular pathway for ADHD research.

Darcq E, Kieffer BL - EMBO Mol Med (2015)

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Faculty of Medicine, Douglas Hospital Research Center, McGill University, Montreal, QC, Canada.

ABSTRACT

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder characterized by hyperactivity, inattention, and impulsive behaviors and has significant societal impact. ADHD is recognized as a heterogeneous disease, and genetic and/or environmental factors underlying pathogenesis remain largely unknown. There is an obvious need to increase knowledge on molecular signaling and brain pathways underlying disease development, and genetic mouse models are key to this goal. In this issue of EMBO Molecular Medicine, D'Andrea et al (2015) combine state-of-the-art genetic and behavioral approaches in the mouse to demonstrate an essential role for PI3Kγ and cAMP homeostasis in ADHD-related behaviors, through signaling mechanisms operating at the level of the locus coeruleus, the main source of noradrenaline in the brain. Furthermore, the study posits PI3Kγ knockout mice as a novel tool of high interest for modeling ADHD endophenotypes.

No MeSH data available.


Related in: MedlinePlus

Role for PI3Kγ signaling in core symptoms of ADHDPI3Kγ is abundant in noradrenergic neurons of the locus coeruleus (LC), which constitute the main source of noradrenaline in the brain. PI3Kγ gene KO in the mouse leads to increased CREB activation via elevation of cAMP levels in the LC and alters the dopamine/noradrenaline (DA/NA) balance in projection areas (prefrontal cortex and striatum). Those modifications facilitate the development of core ADHD-related phenotypes, including hyperactivity and attention deficits, as well as secondary features such as memory and social impairments. Overexpression of CREB in the LC of normal animals produces similar behavioral changes, and down-regulation of CREB activity in the LC of mutant mice reverses the phenotype.
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fig01: Role for PI3Kγ signaling in core symptoms of ADHDPI3Kγ is abundant in noradrenergic neurons of the locus coeruleus (LC), which constitute the main source of noradrenaline in the brain. PI3Kγ gene KO in the mouse leads to increased CREB activation via elevation of cAMP levels in the LC and alters the dopamine/noradrenaline (DA/NA) balance in projection areas (prefrontal cortex and striatum). Those modifications facilitate the development of core ADHD-related phenotypes, including hyperactivity and attention deficits, as well as secondary features such as memory and social impairments. Overexpression of CREB in the LC of normal animals produces similar behavioral changes, and down-regulation of CREB activity in the LC of mutant mice reverses the phenotype.

Mentions: D'Andrea et al then focused on the LC and dissected PI3Kγ downstream signaling events that may contribute to the ADHD phenotype. PI3Kγ signaling involves two pathways, a kinase-dependent and a kinase-independent activity, the former requiring the catalytically active kinase and generation of phosphoinositide (3,4,5)-trisphosphate (PIP3) and the latter acting principally to regulate cAMP levels in a phosphodiesterase (PDE)-specific manner (Patrucco et al, 2004). First, the authors found that knockin mice expressing a kinase-dead (KD) form of PI3Kγ show no behavioral alteration, indicating that ADHD-related behaviors observed in PI3Kγ KO mice recruit the kinase-independent/cAMP pathway. Second, biochemical analysis of PI3Kγ in KO mice revealed modifications of the entire cAMP pathway in the LC, including increased cAMP levels via PDE4D in both cytosolic and membrane compartments of NA neurons, increased phosphorylation of the transcription factor cAMP response binding protein (CREB), as well as increased noradrenaline, and decreased dopamine in LC projection areas, including striatum and prefrontal cortex. Third, virally mediated overexpression of a dominant-negative form of CREB in the LC reversed the ADHD-like phenotypes of PI3Kγ KO mice to wild-type levels and restored NA/DA unbalance in their striatum and prefrontal cortex. Fourth, overexpression of a constitutive active form of CREB in the LC of wild-type mice induced behavioral alterations, similar to those observed in PI3Kγ KO mice, including attention-deficit, hyperactivity, and altered NA/DA in the prefrontal cortex and striatum. The authors conclude that PI3Kγ regulates ADHD-related behaviors via a kinase-independent but CREB-dependent mechanism in noradrenergic neurons of the LC, which controls NA/DA in prefrontal cortex and striatum (Fig1). Identification of this signaling pathway as a key player in the control of NA neuron activities opens attractive perspectives in ADHD research and may prove important in the broad area of developmental brain disorders.


PI3K signaling in the locus coeruleus: a new molecular pathway for ADHD research.

Darcq E, Kieffer BL - EMBO Mol Med (2015)

Role for PI3Kγ signaling in core symptoms of ADHDPI3Kγ is abundant in noradrenergic neurons of the locus coeruleus (LC), which constitute the main source of noradrenaline in the brain. PI3Kγ gene KO in the mouse leads to increased CREB activation via elevation of cAMP levels in the LC and alters the dopamine/noradrenaline (DA/NA) balance in projection areas (prefrontal cortex and striatum). Those modifications facilitate the development of core ADHD-related phenotypes, including hyperactivity and attention deficits, as well as secondary features such as memory and social impairments. Overexpression of CREB in the LC of normal animals produces similar behavioral changes, and down-regulation of CREB activity in the LC of mutant mice reverses the phenotype.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4520651&req=5

fig01: Role for PI3Kγ signaling in core symptoms of ADHDPI3Kγ is abundant in noradrenergic neurons of the locus coeruleus (LC), which constitute the main source of noradrenaline in the brain. PI3Kγ gene KO in the mouse leads to increased CREB activation via elevation of cAMP levels in the LC and alters the dopamine/noradrenaline (DA/NA) balance in projection areas (prefrontal cortex and striatum). Those modifications facilitate the development of core ADHD-related phenotypes, including hyperactivity and attention deficits, as well as secondary features such as memory and social impairments. Overexpression of CREB in the LC of normal animals produces similar behavioral changes, and down-regulation of CREB activity in the LC of mutant mice reverses the phenotype.
Mentions: D'Andrea et al then focused on the LC and dissected PI3Kγ downstream signaling events that may contribute to the ADHD phenotype. PI3Kγ signaling involves two pathways, a kinase-dependent and a kinase-independent activity, the former requiring the catalytically active kinase and generation of phosphoinositide (3,4,5)-trisphosphate (PIP3) and the latter acting principally to regulate cAMP levels in a phosphodiesterase (PDE)-specific manner (Patrucco et al, 2004). First, the authors found that knockin mice expressing a kinase-dead (KD) form of PI3Kγ show no behavioral alteration, indicating that ADHD-related behaviors observed in PI3Kγ KO mice recruit the kinase-independent/cAMP pathway. Second, biochemical analysis of PI3Kγ in KO mice revealed modifications of the entire cAMP pathway in the LC, including increased cAMP levels via PDE4D in both cytosolic and membrane compartments of NA neurons, increased phosphorylation of the transcription factor cAMP response binding protein (CREB), as well as increased noradrenaline, and decreased dopamine in LC projection areas, including striatum and prefrontal cortex. Third, virally mediated overexpression of a dominant-negative form of CREB in the LC reversed the ADHD-like phenotypes of PI3Kγ KO mice to wild-type levels and restored NA/DA unbalance in their striatum and prefrontal cortex. Fourth, overexpression of a constitutive active form of CREB in the LC of wild-type mice induced behavioral alterations, similar to those observed in PI3Kγ KO mice, including attention-deficit, hyperactivity, and altered NA/DA in the prefrontal cortex and striatum. The authors conclude that PI3Kγ regulates ADHD-related behaviors via a kinase-independent but CREB-dependent mechanism in noradrenergic neurons of the LC, which controls NA/DA in prefrontal cortex and striatum (Fig1). Identification of this signaling pathway as a key player in the control of NA neuron activities opens attractive perspectives in ADHD research and may prove important in the broad area of developmental brain disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Faculty of Medicine, Douglas Hospital Research Center, McGill University, Montreal, QC, Canada.

ABSTRACT

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder characterized by hyperactivity, inattention, and impulsive behaviors and has significant societal impact. ADHD is recognized as a heterogeneous disease, and genetic and/or environmental factors underlying pathogenesis remain largely unknown. There is an obvious need to increase knowledge on molecular signaling and brain pathways underlying disease development, and genetic mouse models are key to this goal. In this issue of EMBO Molecular Medicine, D'Andrea et al (2015) combine state-of-the-art genetic and behavioral approaches in the mouse to demonstrate an essential role for PI3Kγ and cAMP homeostasis in ADHD-related behaviors, through signaling mechanisms operating at the level of the locus coeruleus, the main source of noradrenaline in the brain. Furthermore, the study posits PI3Kγ knockout mice as a novel tool of high interest for modeling ADHD endophenotypes.

No MeSH data available.


Related in: MedlinePlus