| First Author | D'Andrea I | Year | 2015 |
| Journal | EMBO Mol Med | Volume | 7 |
| Issue | 7 | Pages | 904-17 |
| PubMed ID | 25882071 | Mgi Jnum | J:233485 |
| Mgi Id | MGI:5784825 | Doi | 10.15252/emmm.201404697 |
| Citation | D'Andrea I, et al. (2015) Lack of kinase-independent activity of PI3Kgamma in locus coeruleus induces ADHD symptoms through increased CREB signaling. EMBO Mol Med 7(7):904-17 |
| abstractText | Although PI3Kgamma 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 PI3Kgamma is present in neurons and that the lack of PI3Kgamma 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 PI3Kgamma 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 PI3Kgamma KO mice resembling ADHD symptoms. PI3Kgamma 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 PI3Kgamma-PDE4D interaction in the noradrenergic neurons of the locus coeruleus, thus uncovering new tools for mechanistic and therapeutic research in ADHD. |
