Dysregulation of the norepinephrine transporter sustains cortical hypodopaminergia and schizophrenia-like behaviors in neuronal rictor null mice.

Michael A Siuta,Sabrina D Robertson,Gregg D Stanwood,Mark A Magnuson,Christine Saunders,Aurelio Galli,Vivek Khatri,Kevin D Niswender,Heidi Kocalis,Lynette C Daws,Daniel B Polley,Jeremy Veenstra-Vanderweele,Paul J Gresch,Chiyo Shiota,Craig W Lindsley,J Philip Kennedy,Eric Nestler

doi:10.1371/journal.pbio.1000393

Abstract

Author SummarySchizophrenia is a disorder caused by multiple genetic and environmental variables. Despite the disease's heterogeneous causes, current hypotheses suggest that dysfunction of dopamine signaling in the brain is one of the final common pathways involved. One gene that may be involved encodes the protein kinase Akt, which is regulated by hormones, growth factors, and neurotransmitter receptors. In this study, we examined the potential molecular mechanisms linking Akt dysregulation to cortical hypodopaminergia, and ultimately to the pathology of schizophrenia. Using transgenic technology, we generated a mouse model with defective neuronal Akt signaling. Neurochemical and behavioral phenotypes associated with schizophrenia include decreases in prefrontal dopamine signaling and deficits in sensorimotor gating, two phenotypes we observed in our transgenic animals. Further, we observed that impaired cortical Akt activity significantly enhanced norepinephrine transporter function. Interestingly, we found that by blocking this transporter, we could reverse the cortical hypodopaminergia and behavioral deficits seen in our transgenic mice. The norepinephrine transporter is a presynaptic membrane protein that is critical for maintaining both norepinephrine and cortical dopamine homeostasis. Taken together, this work supports the potential for targeting both Akt and the norepinephrine transporter for treating dopamine-related mood disorders.

Highlights

Mammalian target of rapamycin complex 2 is one of two highly conserved protein kinases that are critical regulators of cell growth and metabolism. mTOR complex 1 and mTOR complex 2 (mTORC2) are functionally distinct multiprotein complexes that are defined by their subunit composition, rapamycin sensitivity, and substrate selectivity
Despite the disease’s heterogeneous causes, current hypotheses suggest that dysfunction of dopamine signaling in the brain is one of the final common pathways involved
One gene that may be involved encodes the protein kinase Akt, which is regulated by hormones, growth factors, and neurotransmitter receptors

Summary

Introduction

Mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is one of two highly conserved protein kinases that are critical regulators of cell growth and metabolism. mTOR complex 1 (mTORC1) and mTORC2 are functionally distinct multiprotein complexes that are defined by their subunit composition, rapamycin sensitivity, and substrate selectivity. Mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is one of two highly conserved protein kinases that are critical regulators of cell growth and metabolism. MTOR complex 1 (mTORC1) and mTORC2 are functionally distinct multiprotein complexes that are defined by their subunit composition, rapamycin sensitivity, and substrate selectivity. Two key substrates of mTORC1 are S6K and 4E-BP, which are important regulators of translation, while protein kinase B, known as Akt, is the primary substrate of mTORC2 [1]. Post-mortem, imaging, and genetic association studies in humans [3,4,5] reveal that Akt deficiencies are associated with schizophrenia. Genetic studies in rodents further corroborate the relationship between dysregulation in Akt signaling and disruptions in dopamine (DA)-associated behaviors linked to schizophrenia [4,6]

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