A joint project of the Graduate School, Peabody College, and the Jean & Alexander Heard Library

Title page for ETD etd-07132010-191657


Type of Document Dissertation
Author Robertson, Sabrina Elizabeth
URN etd-07132010-191657
Title The role of insulin and Akt in the regulation of the norepinephrine transporter and monoamine homeostasis
Degree PhD
Department Neuroscience
Advisory Committee
Advisor Name Title
Roger Colbran Committee Chair
Anne Kenworthy Committee Member
Aurelio Galli Committee Member
Randy Blakely Committee Member
Keywords
  • diabetes
  • dopamine
  • depression
  • schizophrenia
  • monoamine
  • AKT
  • insulin
  • transporter
  • norepinephrine
Date of Defense 2010-07-06
Availability unrestricted
Abstract
Monoamine signaling in the central nervous system plays an essential role in circuits involving attention, mood, memory, and stress as well as providing pivotal support for autonomic function in the peripheral nervous system. The high affinity norepinephrine (NE) transporter (NET) is the primary mechanism by which noradrenergic synaptic transmission is terminated. Data indicates that NET function is regulated by insulin, a hormone critical for the regulation of metabolism. Given the high co-morbidity of metabolic disorders such as diabetes and obesity with mental disorders such as depression and schizophrenia we sought to determine how insulin signaling regulates NET function and noradrenergic homeostasis. We show that insulin, through the downstream kinase protein kinase B (Akt), significantly decreases NET surface expression in mouse hippocampal slices and superior cervical ganglion neuron (SCGN) boutons (sites of synaptic NE release). In vivo manipulation of insulin/Akt signaling, with streptozotocin (STZ), a drug that induces a Type 1-like diabetic state in mice, also results in aberrant NET function and NE homeostasis. These data suggest that peripheral disruptions in Akt signaling such as in diabetes and obesity have the potential to alter NET function and noradrenergic tone in the brain.

To investigate more specifically the ability of Akt to impact NET function, monoamine homeostasis, and behavior, we disrupted its function independent of insulin signaling. We used conditional gene targeting in mice to eliminate the mammalian target of rapamycin (mTOR) complex 2 (mTORC2) regulatory protein rictor in neurons, leading to impairments in neuronal Akt Ser473 phosphorylation. Importantly, defective Akt phosphorylation at the Ser473 site has been linked to schizophrenia. Here, Rictor-null (KO) mice exhibit prepulse inhibition (PPI) deficits, a schizophrenia-associated behavior, as well as decreased prefrontal dopamine (DA) content, elevated cortical NE, and enhanced expression of NET. In addition, NET blockade in rictor KO mice reverses cortical deficits in DA content and PPI, suggesting that dysregulation of DA homeostasis is driven by alteration in NET expression. Thus, 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 hallmarks of the disorder, cortical hypodopaminergia and hypofunction.

Files
  Filename       Size       Approximate Download Time (Hours:Minutes:Seconds) 
 
 28.8 Modem   56K Modem   ISDN (64 Kb)   ISDN (128 Kb)   Higher-speed Access 
  Sabrina_Robertson_Final_Draft.pdf 3.86 Mb 00:17:51 00:09:10 00:08:02 00:04:01 00:00:20

Browse All Available ETDs by ( Author | Department )

If you have more questions or technical problems, please Contact LITS.