Lack of kinase‐independent activity of PI3Kγ in locus coeruleus induces ADHD symptoms through increased CREB signaling

• Published in: EMBO molecular medicine Vol. 7; no. 7; pp. 904 - 917
• Main Authors: D'Andrea, Ivana, Fardella, Valentina, Fardella, Stefania, Pallante, Fabio, Ghigo, Alessandra, Iacobucci, Roberta, Maffei, Angelo, Hirsch, Emilio, Lembo, Giuseppe, Carnevale, Daniela
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2015; EMBO Press; John Wiley & Sons, Ltd
• Subjects: Adrenergic Neurons - pathology; Animals; Attention Deficit Disorder with Hyperactivity - pathology; Attention Deficit Disorder with Hyperactivity - physiopathology; Attention deficit hyperactivity disorder; Behavioral plasticity; Brain research; Brain stem; Cardiovascular diseases; catecholamine; Class Ib Phosphatidylinositol 3-Kinase - metabolism; CREB; Cyclic AMP response element-binding protein; Cyclic AMP Response Element-Binding Protein - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism; Disease Models, Animal; Dopamine; EMBO27; Enzymes; Experiments; Flexibility; Genotype & phenotype; Hyperactivity; Kinases; Locomotion; Locus coeruleus; Locus Coeruleus - pathology; Locus Coeruleus - physiopathology; Memory; Mental disorders; Mice; Mice, Knockout; Microsurgery; mouse model; Neurons; Norepinephrine; Phenotypes; Phosphodiesterase; phosphodiesterases (PDEs); Protein Binding; Proteins; Research Article; Signal Transduction; Statistical analysis; stereotactic surgery; Synaptic plasticity; catecholamine; CREB; mouse model; stereotactic surgery; phosphodiesterases (PDEs)
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.201404697

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. Synopsis PI3K regulates synaptic plasticity and behavioral flexibility via a kinase‐independent but CREB‐dependent mechanism in noradrenergic neurons of the locus coeruleus. PI3Kγ‐deficient mice model main features of attention‐deficit/hyperactivity disorders (ADHD). PI3Kγ KO mice exhibit symptomatic traits of the attention‐deficit/hyperactivity disorder (ADHD), displaying deficits in the attentive and mnemonic domains, coupled with typical hyperactivity, as well as social dysfunctions. PI3Kγ controls locus coeruleus (LC) functions in the modulations of these behavioral domains by kinase‐independent mechanisms; the PI3Kγ KD (kinase‐defective) mice are not affected. PI3Kγ physically interacts with phosphodiesterase 4D (PDE4D) in the LC and controls cAMP–CREB signaling, which is constitutively increased in PI3Kγ KO mice. Selective genetic targeting of increased CREB signaling in the LC by stereotactic approach rescues the ADHD phenotype of PI3Kγ KO mice. Graphical Abstract PI3K regulates synaptic plasticity and behavioral flexibility via a kinase‐independent but CREB‐dependent mechanism in noradrenergic neurons of the locus coeruleus. PI3Kγ‐deficient mice model main features of attention‐deficit/hyperactivity disorders (ADHD).