Decreased AKT1/mTOR pathway mRNA expression in short-term bipolar disorder.
Strong evidence implicates intracellular signaling cascades dysfunction in the pathophysiology of Bipolar Disorder (BD). Regulation of AKT/mTOR pathway is a critical signaling pathway in synaptic neurotransmission and plasticity, also modulating cell proliferation and migration. Gene expression of the AKT/mTOR pathway was assessed in 25 BD (DSM-IV-TR criteria) unmedicated depressed individuals at baseline and after 6 weeks of lithium therapy and 31 matched healthy controls. Decreases in blood AKT1 and mTOR mRNA expression, as well as in BAD/BCL-2 expression ratio were observed in short-term BD patients during depressive episodes in comparison to healthy controls. There was no significant change in the expression of AKT1, mTOR, BCL-2, BAD and NDUFA6 after lithium therapy in the total group of BD subjects. However, the changes in AKT1 expression after lithium treatment were positively correlated with depression improvement. An integrated activity within this pathway was observed at both baseline and post-treatment. The present results support an integrated AKT/mTOR signaling pathway activity in a similar fashion to the described in previous human postmortem and rodents brain studies. Overall, the results reinforce a role for AKT1 and mTOR in the pathophysiology of BD and support the relevance of blood mRNA expression as a valid surrogate biological source to study brain intracellular signaling cascades changes and convergent molecular pathways in psychiatric disorders.
Laboratory of Neuroscience, LIM- 27, Institute and Department of Psychiatry, University of Sao Paulo, Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of Sao Paulo, Brazil; Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, NIH, Bethesda, MD, United States. Electronic address: machadovieirar@gmail.com.
Rodrigo
R
Machado-Vieira
Laboratory of Neuroscience, LIM- 27, Institute and Department of Psychiatry, University of Sao Paulo, Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of Sao Paulo, Brazil.
Marcus V
MV
Zanetti
Interdisciplinary Laboratory of Medical Investigation, Federal University of Minas Gerais, Brazil.
Antonio L
AL
Teixeira
Laboratory of Molecular and Cellular Biology, Department of Neurology, University of Sao Paulo, Brazil.
Miyuki
M
Uno
Laboratory of Neuroscience, LIM- 27, Institute and Department of Psychiatry, University of Sao Paulo, Brazil.
Leandro L
LL
Valiengo
Mood Disorders Program, GRUDA, Department of Psychiatry, University of Sao Paulo, Brazil.
Marcio G
MG
Soeiro-de-Souza
Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, NIH, Bethesda, MD, United States.
Sueli M
SM
Oba-Shinjo
Laboratory of Neuroscience, LIM- 27, Institute and Department of Psychiatry, University of Sao Paulo, Brazil.
Rafael T
RT
de Sousa
Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, NIH, Bethesda, MD, United States.
Carlos A
CA
Zarate
Laboratory of Neuroscience, LIM- 27, Institute and Department of Psychiatry, University of Sao Paulo, Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of Sao Paulo, Brazil.
Wagner F
WF
Gattaz
Laboratory of Molecular and Cellular Biology, Department of Neurology, University of Sao Paulo, Brazil.
Suely K N
SK
Marie
D000293:Adolescent; D000328:Adult; D018692:Antimanic Agents / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects / Q000235:genetics; D006801:Humans; D018021:Lithium Chloride / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009245:NADH Dehydrogenase / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D018709:Statistics, Nonparametric; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D055815:Young Adult; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism
D018692:Antimanic Agents; C494819:BAD protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051025:bcl-Associated Death Protein; D009245:NADH Dehydrogenase; C546842:MTOR protein, human; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D018021:Lithium Chloride
AKT; Bipolar disorder; Depression; Lithium; Treatment; mTOR