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. 2015 Apr 16;7(7):904–917. doi: 10.15252/emmm.201404697

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

Ivana D'Andrea 1,†, Valentina Fardella 1,†, Stefania Fardella 1, Fabio Pallante 1, Alessandra Ghigo 2, Roberta Iacobucci 1, Angelo Maffei 1, Emilio Hirsch 2, Giuseppe Lembo 1,3,*, Daniela Carnevale 1,3,**
PMCID: PMC4520656  PMID: 25882071

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.

Keywords: catecholamine, CREB, mouse model, phosphodiesterases (PDEs), stereotactic surgery

See also: E Darcq & BL Kieffer (July 2015)

Supporting Information

Supplementary Figure S1

emmm0007-0904-sd1.tif (1.1MB, tif)

Supplementary Figure S2

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Supplementary Figure S3

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Supplementary Figure S4

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Supplementary Figure S6

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Supplementary Figure S7

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Supplementary Figure S8

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Supplementary Figure S9

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Supplementary Figure S10

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Supplementary Figure S11

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Supplementary Figure S12

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Supplementary Table S1

emmm0007-0904-sd13.pdf (117.5KB, pdf)

Supplementary Table S2

emmm0007-0904-sd14.pdf (92.5KB, pdf)

Supplementary Table S3

emmm0007-0904-sd15.pdf (101.9KB, pdf)

Review Process File

emmm0007-0904-sd16.pdf (358KB, pdf)

Source Data for Figure 3E

emmm0007-0904-sd17.jpg (204.7KB, jpg)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Figure S1

emmm0007-0904-sd1.tif (1.1MB, tif)

Supplementary Figure S2

emmm0007-0904-sd2.tif (2.1MB, tif)

Supplementary Figure S3

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Supplementary Figure S4

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Supplementary Figure S5

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Supplementary Figure S6

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Supplementary Figure S7

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Supplementary Figure S8

emmm0007-0904-sd8.tif (916.7KB, tif)

Supplementary Figure S9

emmm0007-0904-sd9.tif (1.4MB, tif)

Supplementary Figure S10

emmm0007-0904-sd10.tif (1.5MB, tif)

Supplementary Figure S11

emmm0007-0904-sd11.tif (1.4MB, tif)

Supplementary Figure S12

emmm0007-0904-sd12.tif (1.3MB, tif)

Supplementary Table S1

emmm0007-0904-sd13.pdf (117.5KB, pdf)

Supplementary Table S2

emmm0007-0904-sd14.pdf (92.5KB, pdf)

Supplementary Table S3

emmm0007-0904-sd15.pdf (101.9KB, pdf)

Review Process File

emmm0007-0904-sd16.pdf (358KB, pdf)

Source Data for Figure 3E

emmm0007-0904-sd17.jpg (204.7KB, jpg)

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