Targeting Kruppel-like Factor 9 in Excitatory Neurons Protects against Chronic Stress-Induced Impairments in Dendritic Spines and Fear Responses
Antoine Besnard,
Tomer Langberg,
Sally Levinson,
Duong Chu,
Cinzia Vicidomini,
Kimberly N. Scobie,
Andrew J. Dwork,
Victoria Arango,
Gorazd B. Rosoklija,
J. John Mann,
René Hen,
E. David Leonardo,
Maura Boldrini,
Amar Sahay
Affiliations
Antoine Besnard
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA
Tomer Langberg
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA
Sally Levinson
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA
Duong Chu
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA
Cinzia Vicidomini
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA
Kimberly N. Scobie
Department of Psychiatry, Columbia University Medical Center, New York, NY 10032, USA
Andrew J. Dwork
Department of Psychiatry, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Divisions of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, NY 10032, USA; Macedonian Academy of Sciences & Arts, Skopje 1000, Republic of Macedonia
Victoria Arango
Department of Psychiatry, Columbia University Medical Center, New York, NY 10032, USA; Divisions of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, NY 10032, USA
Gorazd B. Rosoklija
Department of Psychiatry, Columbia University Medical Center, New York, NY 10032, USA; Divisions of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, NY 10032, USA; Macedonian Academy of Sciences & Arts, Skopje 1000, Republic of Macedonia
J. John Mann
Department of Psychiatry, Columbia University Medical Center, New York, NY 10032, USA; Divisions of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, NY 10032, USA
René Hen
Department of Psychiatry, Columbia University Medical Center, New York, NY 10032, USA; Department of Neuroscience, Columbia University Medical Center, New York, NY 10032, USA; Department of Pharmacology, Columbia University Medical Center, New York, NY 10032, USA; Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, NY 10032, USA
E. David Leonardo
Department of Psychiatry, Columbia University Medical Center, New York, NY 10032, USA
Maura Boldrini
Department of Psychiatry, Columbia University Medical Center, New York, NY 10032, USA; Divisions of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, NY 10032, USA
Amar Sahay
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA; BROAD Institute of Harvard and MIT, Cambridge, MA 02142, USA; Corresponding author
Summary: Stress exposure is associated with the pathogenesis of psychiatric disorders, including post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). Here, we show in rodents that chronic stress exposure rapidly and transiently elevates hippocampal expression of Kruppel-like factor 9 (Klf9). Inducible genetic silencing of Klf9 expression in excitatory forebrain neurons in adulthood prior to, but not after, onset of stressor prevented chronic restraint stress (CRS)-induced potentiation of contextual fear acquisition in female mice and chronic corticosterone (CORT) exposure-induced fear generalization in male mice. Klf9 silencing prevented chronic CORT and CRS induced enlargement of dendritic spines in the ventral hippocampus of male and female mice, respectively. KLF9 mRNA density was increased in the anterior dentate gyrus of women, but not men, with more severe recent stressful life events and increased mortality. Thus, Klf9 functions as a stress-responsive transcription factor that mediates circuit and behavioral resilience in a sex-specific manner. : Besnard et al. show that chronic stress induces a transient elevation in hippocampal Klf9 expression in mice and that KLF9 expression is upregulated in hippocampus of women with MDD. Genetic silencing of Klf9 expression prevents chronic stress-induced enlargements of dendritic spines and maladaptive fear responses in male and female mice. Keywords: stress, dendritic spines, fear generalization, hippocampus, Klf9, dentate gyrus, CA1, PTSD, MDD, corticosterone
