Dysregulation of the norepinephrine transporter sustains cortical hypodopaminergia and schizophrenia-like behaviors in neuronal rictor null mice.
The mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is a multimeric signaling unit that phosphorylates protein kinase B/Akt following hormonal and growth factor stimulation. Defective Akt phosphorylation at the mTORC2-catalyzed Ser473 site has been linked to schizophrenia. While human imaging and animal studies implicate a fundamental role for Akt signaling in prefrontal dopaminergic networks, the molecular mechanisms linking Akt phosphorylation to specific schizophrenia-related neurotransmission abnormalities have not yet been described. Importantly, current understanding of schizophrenia suggests that cortical decreases in DA neurotransmission and content, defined here as cortical hypodopaminergia, contribute to both the cognitive deficits and the negative symptoms characteristic of this disorder. We sought to identify a mechanism linking aberrant Akt signaling to these hallmarks of schizophrenia. We used conditional gene targeting in mice to eliminate the mTORC2 regulatory protein rictor in neurons, leading to impairments in neuronal Akt Ser473 phosphorylation. Rictor-null (KO) mice exhibit prepulse inhibition (PPI) deficits, a schizophrenia-associated behavior. In addition, they show reduced prefrontal dopamine (DA) content, elevated cortical norepinephrine (NE), unaltered cortical serotonin (5-HT), and enhanced expression of the NE transporter (NET). In the cortex, NET takes up both extracellular NE and DA. Thus, we propose that amplified NET function in rictor KO mice enhances accumulation of both NE and DA within the noradrenergic neuron. This phenomenon leads to conversion of DA to NE and ultimately supports both increased NE tissue content as well as a decrease in DA. In support of this hypothesis, NET blockade in rictor KO mice reversed cortical deficits in DA content and PPI, suggesting that dysregulation of DA homeostasis is driven by alteration in NET expression, which we show is ultimately influenced by Akt phosphorylation status. These data illuminate a molecular link, Akt regulation of NET, between the recognized association of Akt signaling deficits in schizophrenia with a specific mechanism for cortical hypodopaminergia and hypofunction. Additionally, our findings identify Akt as a novel modulator of monoamine homeostasis in the cortex.
Siuta
Michael A
MA
Center for Molecular Neuroscience, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Robertson
Sabrina D
SD
Kocalis
Heidi
H
Saunders
Christine
C
Gresch
Paul J
PJ
Khatri
Vivek
V
Shiota
Chiyo
C
Kennedy
J Philip
JP
Lindsley
Craig W
CW
Daws
Lynette C
LC
Polley
Daniel B
DB
Veenstra-Vanderweele
Jeremy
J
Stanwood
Gregg D
GD
Magnuson
Mark A
MA
Niswender
Kevin D
KD
Galli
Aurelio
A
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000502:physiology*; D010766:Phosphorylation; D017397:Prefrontal Cortex / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D012559:Schizophrenia / Q000503:physiopathology*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors
D002352:Carrier Proteins; C504923:Crtc2 protein, mouse; D050484:Norepinephrine Plasma Membrane Transport Proteins; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015534:Trans-Activators; D014157:Transcription Factors; C525637:rictor protein, mouse; D012694:Serine; D051057:Proto-Oncogene Proteins c-akt; D004298:Dopamine