Fibroblast growth factor 9 is a novel modulator of negative affect.
Both gene expression profiling in postmortem human brain and studies using animal models have implicated the fibroblast growth factor (FGF) family in affect regulation and suggest a potential role in the pathophysiology of major depressive disorder (MDD). FGF2, the most widely characterized family member, is down-regulated in the depressed brain and plays a protective role in rodent models of affective disorders. By contrast, using three microarray analyses followed by quantitative RT-PCR confirmation, we show that FGF9 expression is up-regulated in the hippocampus of individuals with MDD, and that FGF9 expression is inversely related to the expression of FGF2. Because little is known about FGF9's function in emotion regulation, we used animal models to shed light on its potential role in affective function. We found that chronic social defeat stress, an animal model recapitulating some aspects of MDD, leads to a significant increase in hippocampal FGF9 expression, paralleling the elevations seen in postmortem human brain tissue. Chronic intracerebroventricular administration of FGF9 increased both anxiety- and depression-like behaviors. In contrast, knocking down FGF9 expression in the dentate gyrus of the hippocampus using a lentiviral vector produced a decrease in FGF9 expression and ameliorated anxiety-like behavior. Collectively, these results suggest that high levels of hippocampal FGF9 play an important role in the development or expression of mood and anxiety disorders. We propose that the relative levels of FGF9 in relation to other members of the FGF family may prove key to understanding vulnerability or resilience in affective disorders.
Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109; Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109;
Elyse L
EL
Aurbach
Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109;
Edny Gula
EG
Inui
Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109;
Cortney A
CA
Turner
Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109;
Megan H
MH
Hagenauer
Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109; Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109;
Katherine E
KE
Prater
Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109;
Jun Z
JZ
Li
Department of Psychiatry & Human Behavior, University of California, Irvine, CA 92697;
Devin
D
Absher
Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109;
Najmul
N
Shah
Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109;
Peter
P
Blandino
Department of Psychiatry & Human Behavior, University of California, Irvine, CA 92697;
William E
WE
Bunney
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806;
Richard M
RM
Myers
Department of Psychiatry, Cornell University, New York, NY 10065;
Jack D
JD
Barchas
Department of Psychiatry, Stanford University, Stanford, CA 94305.
Alan F
AF
Schatzberg
Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109;
Stanley J
SJ
Watson
Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109; akil@umich.edu.
Huda
H
Akil
D000328:Adult; D000339:Affect / Q000187:drug effects; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001007:Anxiety / Q000150:complications / Q000378:metabolism; D001362:Avoidance Learning / Q000187:drug effects; D016022:Case-Control Studies; D003710:Demography; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism; D003865:Major Depressive Disorder / Q000150:complications / Q000378:metabolism; D005260:Female; D051525:Fibroblast Growth Factor 9 / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D016086:Lentivirus / Q000378:metabolism; D008297:Male; D008845:Microinjections; D008875:Middle Aged; D011180:Postmortem Changes; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D013315:Stress, Psychological / Q000150:complications / Q000235:genetics; D055815:Young Adult
D051525:Fibroblast Growth Factor 9; D034741:RNA, Small Interfering; D051496:Receptor, Fibroblast Growth Factor, Type 1
affect; anxiety; fibroblast growth factor 9; hippocampus; major depression