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.

Highlights

  • Phosphoinositide 3-kinases (PI3Ks) are intracellular signaling enzymes activated by various cell-surface receptors, modulating important cellular functions, such as cell survival, proliferation, migration and adhesion (Toker & Cantley, 1997; Bondeva et al, 1998)

  • We aimed at assessing the role of PI3Kc signaling on the behavioral states regulated by the locus coeruleus (LC) and, in order to accomplish this issue, we performed a series of behavioral tests that engage this pathway (Supplementary Table S1)

  • We investigated the cognitive responses of PI3Kc KO mice in the attentional domain, through attentional set-shifting (ASS) test

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Summary

Introduction

Phosphoinositide 3-kinases (PI3Ks) are intracellular signaling enzymes activated by various cell-surface receptors, modulating important cellular functions, such as cell survival, proliferation, migration and adhesion (Toker & Cantley, 1997; Bondeva et al, 1998). PI3Kc has been extensively investigated in inflammatory and cardiovascular diseases, the exploration of its functions in the brain is just at dawning. On this issue, many years ago, it has been shown that PI3Kc is present in neurons and that its Akt/PKB signaling is required for the potentiation of L-type channels and for changes in neuronal excitability (Viard et al, 2004). It has been shown that the lack of PI3Kc in mice leads to an impairment in synaptic plasticity, associated with alterations suggestive of a role in mediating behavioral flexibility (Kim et al, 2011)

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