title: Lack of kinase-independent activity of PI3Kγ in locus coeruleus induces ADHD symptoms through increased CREB signaling.
abstract: Although PI3Kγ has been extensively investigated in inflammatory and cardiovascular diseases, the exploration of its functions in the brain is just at dawning. It is known that PI3Kγ is present in neurons and that the lack of PI3Kγ in mice leads to impaired synaptic plasticity, suggestive of a role in behavioral flexibility. Several neuropsychiatric disorders, such as attention-deficit/hyperactivity disorder (ADHD), involve an impairment of behavioral flexibility. Here, we found a previously unreported expression of PI3Kγ throughout the noradrenergic neurons of the locus coeruleus (LC) in the brainstem, serving as a mechanism that regulates its activity of control on attention, locomotion and sociality. In particular, we show an unprecedented phenotype of PI3Kγ KO mice resembling ADHD symptoms. PI3Kγ KO mice exhibit deficits in the attentive and mnemonic domains, typical hyperactivity, as well as social dysfunctions. Moreover, we demonstrate that the ADHD phenotype depends on a dysregulation of CREB signaling exerted by a kinase-independent PI3Kγ-PDE4D interaction in the noradrenergic neurons of the locus coeruleus, thus uncovering new tools for mechanistic and therapeutic research in ADHD.
authors.affiliation: Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Pozzilli (IS), Italy.
authors.forename: Ivana
authors.initials: I
authors.lastname: D'Andrea
authors.affiliation: Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Pozzilli (IS), Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Fardella
authors.affiliation: Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Pozzilli (IS), Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Fardella
authors.affiliation: Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Pozzilli (IS), Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Pallante
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ghigo
authors.affiliation: Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Pozzilli (IS), Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Iacobucci
authors.affiliation: Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Pozzilli (IS), Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Maffei
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.affiliation: Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Pozzilli (IS), Italy Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy lembo@neuromed.it daniela.carnevale@neuromed.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lembo
authors.affiliation: Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Pozzilli (IS), Italy Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy lembo@neuromed.it daniela.carnevale@neuromed.it.
authors.forename: Daniela
authors.initials: D
authors.lastname: Carnevale
mesh_terms: D059331:Adrenergic Neurons / Q000473:pathology*; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000473:pathology* / Q000503:physiopathology; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D004195:Disease Models, Animal; D008125:Locus Coeruleus / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D015398:Signal Transduction
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C531980:PDE4D protein, mouse
keywords: CREB; catecholamine; mouse model; phosphodiesterases (PDEs); stereotactic surgery