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

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.

Cross-disorder genetic analyses implicate dopaminergic signaling as a biological link between Attention-Deficit/Hyperactivity Disorder and obesity measures

“…DARPP-32 modulates the effects of dopamine on cAMP/PKAdependent gene transcription through transcription factors of the cyclic AMP-responsive element-binding (CREB) complex (Fig. 1), and CREB dysregulation has been linked to both ADHD [38] and obesity [39]. Of note, the CREB Signaling in Neurons pathway was also significantly enriched in our ADHD-BMI gene-based metaanalysis, along with two other partially overlapping pathways involved in synaptic plasticity processes (namely, the Synaptic Long Term Depression and the Synaptic Long Term Potentiation pathways; Table 2), which are also closely related to dopamine DARPP-32 signaling.…”

Scaffolding Function of PI3Kgamma Emerges from Enzyme's Shadow

“…Kinase-independent functions of PI3Kγ have also been observed in other cell types including platelets[59], endothelial progenitors EPCs[60], microglia[61], and neurons[62] indicating there role in diverse functions.…”

“…Moreover, these studies show that the ADHD phenotype is regulated by kinase-independent function of PI3Kγ through its interaction with PDE4D. In this context, the findings show that ADHD phenotype is due to a dysregulation of CREB signaling exerted by a loss of PI3Kγ in the noradrenergic neurons of the locus coeruleus uncovering novel mechanism and tools for therapeutic research in ADHD[62]. …”

Cross-disorder genetic analyses implicate dopaminergic signaling as a biological link between Attention-Deficit/Hyperactivity Disorder and obesity measures

“…Upon investigation of the consequences of frustrated expected reward of palatable food on gene expression in the mouse brain, Dopamine-DARPP32 Feedback in cAMP Signaling pathway was found to be enriched among differentially expressed genes, both the ventral striatum and in frontal cortex [37]. DARPP-32 modulates the effects of dopamine on cAMP/PKA-dependent gene transcription through transcription factors of the cyclic AMP-responsive element-binding (CREB) complex (Figure 1), and CREB dysregulation has been linked to both ADHD [38] and obesity [39]. Of note, the CREB Signaling in Neurons pathway was also significantly enriched in our ADHD-BMI gene-based meta-analysis, along with two other partially overlapping pathways involved in synaptic plasticity processes (namely, the Synaptic Long Term Depression and the Synaptic Long Term Potentiation pathways; Table 2), which are also closely related to dopamine DARPP-32 signaling.…”