Transglutaminase 2 overexpression induces depressive-like behavior and impaired TrkB signaling in mice.
Serotonin (5-hydroxytryptamine, 5-HT) and brain-derived neurotrophic factor (BDNF) are two signaling molecules that have important regulatory roles in the development and plasticity of neural circuits that are known to be altered in depression. However, the mechanism by which 5-HT regulates BDNF signaling is unknown. In the present study, we found that 5-HT treatment increases BDNF receptor, TrkB (tropomyosin related kinase B), levels in mouse primary cortical neurons via a Rac1 (RAS-related C3 botulinum toxin substrate 1)-dependent mechanism. Significant increases in the levels of type-2 transglutaminase (TG2, which is implicated in transamidation of 5-HT to Rac1) are observed in the mouse prefrontal cortex (PFC) following chronic exposure to stress. We also found that TG2 levels are increased in the post-mortem PFC of depressed suicide subjects relative to matched controls. Moreover, in mice, neuronal overexpression of TG2 resulted in the atrophy of neurons and reduced levels of TrkB in the PFC as well as a depressive-like phenotype. Overexpression of TG2 in mouse cortical neurons reduced TrkB levels as a result of impaired endocytosis of TrkB. TG2 inhibition by either a viral particle or pharmacological approach attenuated behavioral deficits caused by chronic unpredictable stress. Moreover, the overexpression of TrkB in the mouse PFC ameliorated the depressive-like phenotype of TG2-overexpressed mice. Taken together, these post-mortem and preclinical findings identify TG2 as a critical mediator of the altered TrkB expression and depressive-like behaviors associated with chronic exposure to stress and suggest that TG2 may represent a novel therapeutic target in depression.
Department of Psychiatry and Health Behavior, Medical College of Georgia at Augusta University, Augusta, GA, USA.
C D
CD
Pandya
Department of Medical Laboratory, Imaging and Radiologic Sciences, Augusta University, Augusta, GA, USA.
N
N
Hoda
Department of Psychiatry and Health Behavior, Medical College of Georgia at Augusta University, Augusta, GA, USA.
A
A
Crider
Department of Psychiatry and Health Behavior, Medical College of Georgia at Augusta University, Augusta, GA, USA.
D
D
Peter
Department of Psychiatry and Health Behavior, Medical College of Georgia at Augusta University, Augusta, GA, USA.
A
A
Kutiyanawalla
Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA, USA.
S
S
Kumar
Department of Psychiatry, Weill Cornell Medical College, White Plains, NY, USA.
A O
AO
Ahmed
McGill Group for Suicide Studies, Depressive Disorders Program, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
G
G
Turecki
Department of Pharmacology and Toxicology, Medical College of Georgia at Augusta University, Augusta, GA, USA.
C M
CM
Hernandez
Department of Pharmacology and Toxicology, Medical College of Georgia at Augusta University, Augusta, GA, USA.
A V
AV
Terry
Department of Psychiatry and Health Behavior, Medical College of Georgia at Augusta University, Augusta, GA, USA.
A
A
Pillai
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D003863:Depression / Q000201:enzymology* / Q000378:metabolism; D005260:Female; D019204:GTP-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism; D011247:Pregnancy; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012333:RNA, Messenger / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D015398:Signal Transduction; D013405:Suicide; D011503:Transglutaminases / Q000096:biosynthesis* / Q000235:genetics
D019208:Brain-Derived Neurotrophic Factor; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D012701:Serotonin; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D020813:Receptor, trkB; D019204:GTP-Binding Proteins