Lack of kinase-independent activity of PI3K in locus coeruleus induces ADHD symptoms through increased CREB signaling

Although PI3K 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 PI3K is present in neurons and that the lack of PI3K 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 PI3K 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 PI3K KO mice resembling ADHD symptoms. PI3K 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 PI3K-PDE4D interaction in the noradrenergic neurons of the locus coeruleus, thus uncovering new tools for mechanistic and therapeutic research in ADHD.