TY - JOUR
T1 - Neuronal ablation of p-Akt at Ser473 leads to altered 5-HT1A/2A receptor function
AU - Saunders, Christine
AU - Siuta, Michael
AU - Robertson, Sabrina D.
AU - Davis, Adeola R.
AU - Sauer, Jennifer
AU - Matthies, Heinrich J.G.
AU - Gresch, Paul J.
AU - Airey, David C.
AU - Lindsley, Craig W.
AU - Schetz, John A.
AU - Niswender, Kevin D.
AU - Veenstra-Vanderweele, Jeremy M.
AU - Galli, Aurelio
N1 - Funding Information:
This work was supported by National Institutes of Health Grants P50 MH078028-Pilot Project (C.S.), MH063162 (J.A.S.), MH081066 (J.V.), and DK085712 (A.G. and K.D.N.). We thank Amanda Poe for assistance in genotyping and maintaining the mouse colonies. We are very grateful to the Conte Center Bioanalytical Core , specifically to Brett Begely, for his technical skills with the 5-HT receptor and transporter binding studies.
PY - 2014/7
Y1 - 2014/7
N2 - The serotonergic system regulates a wide range of behavior, including mood and impulsivity, and its dysregulation has been associated with mood disorders, autism spectrum disorder, and addiction. Diabetes is a risk factor for these conditions. Insulin resistance in the brain is specifically associated with susceptibility to psychostimulant abuse. Here, we examined whether phosphorylation of Akt, a key regulator of the insulin signaling pathway, controls serotonin (5-HT) signaling. To explore how impairment in Akt function regulates 5-HT homeostasis, we used a brain-specific rictor knockout (KO) mouse model of impaired neuronal phosphorylation of Akt at Ser473. Cortical 5-HT 1A and 5-HT2A receptor binding was significantly elevated in rictor KO mice. Concomitant with this elevated receptor expression, the 5-HT1A receptor agonist 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) led to an increased hypothermic response in rictor KO mice. The increased cortical 5-HT1A receptor density was associated with higher 5-HT1A receptor levels on the cortical cell surface. In contrast, rictor KO mice displayed significantly reduced head-twitch response (HTR) to the 5-HT2A/C agonist 2,5-dimethoxy-4-iodoamphetamine (DOI), with evidence of impaired 5-HT2A/C receptor signaling. In vitro, pharmacological inhibition of Akt significantly increased 5-HT1A receptor expression and attenuated DOI-induced 5-HT2A receptor signaling, thereby lending credence to the observed in vivo cross-talk between neuronal Akt signaling and 5-HT receptor regulation. These data reveal that defective central Akt function alters 5-HT signaling as well as 5-HT-associated behaviors, demonstrating a novel role for Akt in maintaining neuronal 5-HT receptor function.
AB - The serotonergic system regulates a wide range of behavior, including mood and impulsivity, and its dysregulation has been associated with mood disorders, autism spectrum disorder, and addiction. Diabetes is a risk factor for these conditions. Insulin resistance in the brain is specifically associated with susceptibility to psychostimulant abuse. Here, we examined whether phosphorylation of Akt, a key regulator of the insulin signaling pathway, controls serotonin (5-HT) signaling. To explore how impairment in Akt function regulates 5-HT homeostasis, we used a brain-specific rictor knockout (KO) mouse model of impaired neuronal phosphorylation of Akt at Ser473. Cortical 5-HT 1A and 5-HT2A receptor binding was significantly elevated in rictor KO mice. Concomitant with this elevated receptor expression, the 5-HT1A receptor agonist 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) led to an increased hypothermic response in rictor KO mice. The increased cortical 5-HT1A receptor density was associated with higher 5-HT1A receptor levels on the cortical cell surface. In contrast, rictor KO mice displayed significantly reduced head-twitch response (HTR) to the 5-HT2A/C agonist 2,5-dimethoxy-4-iodoamphetamine (DOI), with evidence of impaired 5-HT2A/C receptor signaling. In vitro, pharmacological inhibition of Akt significantly increased 5-HT1A receptor expression and attenuated DOI-induced 5-HT2A receptor signaling, thereby lending credence to the observed in vivo cross-talk between neuronal Akt signaling and 5-HT receptor regulation. These data reveal that defective central Akt function alters 5-HT signaling as well as 5-HT-associated behaviors, demonstrating a novel role for Akt in maintaining neuronal 5-HT receptor function.
KW - Akt
KW - Cortex
KW - Serotonin
UR - http://www.scopus.com/inward/record.url?scp=84902435572&partnerID=8YFLogxK
U2 - 10.1016/j.neuint.2013.09.015
DO - 10.1016/j.neuint.2013.09.015
M3 - Article
C2 - 24090638
AN - SCOPUS:84902435572
SN - 0197-0186
VL - 73
SP - 113
EP - 121
JO - Neurochemistry International
JF - Neurochemistry International
IS - 1
ER -