Open AccessLack of kinase‐independent activity of PI3Kγ in locus coeruleus induces ADHD symptoms through increased CREB signaling
Author(s) -
D'Andrea Ivana,
Fardella Valentina,
Fardella Stefania,
Pallante Fabio,
Ghigo Alessandra,
Iacobucci Roberta,
Maffei Angelo,
Hirsch Emilio,
Lembo Giuseppe,
Carnevale Daniela
Publication year - 2015
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201404697
Subject(s) - locus coeruleus , creb , pi3k/akt/mtor pathway , signal transduction , kinase , neuroscience , microbiology and biotechnology , biology , chemistry , genetics , transcription factor , gene , central nervous system
Although PI 3Kγ 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 PI 3Kγ is present in neurons and that the lack of PI 3Kγ 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 PI 3Kγ 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 PI 3Kγ KO mice resembling ADHD symptoms. PI 3Kγ 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 PI 3Kγ‐ PDE 4D interaction in the noradrenergic neurons of the locus coeruleus, thus uncovering new tools for mechanistic and therapeutic research in ADHD .