Decreased SGK1 Expression and Function Contributes to Behavioral Deficits Induced by Traumatic Stress.
Exposure to extreme stress can trigger the development of major depressive disorder (MDD) as well as post-traumatic stress disorder (PTSD). The molecular mechanisms underlying the structural and functional alterations within corticolimbic brain regions, including the prefrontal cortex (PFC) and amygdala of individuals subjected to traumatic stress, remain unknown. In this study, we show that serum and glucocorticoid regulated kinase 1 (SGK1) expression is down-regulated in the postmortem PFC of PTSD subjects. Furthermore, we demonstrate that inhibition of SGK1 in the rat medial PFC results in helplessness- and anhedonic-like behaviors in rodent models. These behavioral changes are accompanied by abnormal dendritic spine morphology and synaptic dysfunction. Together, the results are consistent with the possibility that altered SGK1 signaling contributes to the behavioral and morphological phenotypes associated with traumatic stress pathophysiology.
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, United States of America; Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Pawel
P
Licznerski
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, United States of America; Department of Physiology and Pharmacology, Des Moines University, Des Moines, Iowa, United States of America.
Vanja
V
Duric
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Mounira
M
Banasr
Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut, United States of America; Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom.
Kambiz N
KN
Alavian
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Kristie T
KT
Ota
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Hyo Jung
HJ
Kang
Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Elizabeth A
EA
Jonas
Department of Psychiatry and Center for the Study of Traumatic Stress, Uniformed Services University of the Health Sciences and for the Traumatic Stress Brain Study Group, Bethesda, Maryland, United States of America.
Robert
R
Ursano
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, United States of America; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut, United States of America; VA National Center for PTSD, VA Connecticut Healthcare System, West Haven, Connecticut, United States of America; Yale-New Haven Hospital, New Haven, Connecticut, United States of America.
John H
JH
Krystal
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, United States of America; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut, United States of America; VA National Center for PTSD, VA Connecticut Healthcare System, West Haven, Connecticut, United States of America.
Ronald S
RS
Duman
D000328:Adult; D000818:Animals; D001522:Behavior, Animal; D015331:Cohort Studies; D049229:Dendritic Spines / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D003865:Major Depressive Disorder / Q000209:etiology*; D004794:Enzyme Repression; D005260:Female; D018014:Gene Transfer Techniques; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D017397:Prefrontal Cortex / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013313:Stress Disorders, Post-Traumatic / Q000378:metabolism* / Q000473:pathology / Q000523:psychology; D009435:Synaptic Transmission; D014015:Tissue Banks; D000099184:Serum-Glucocorticoid Regulated Kinases
D017874:Immediate-Early Proteins; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases