IGFBP2 Produces Rapid-Acting and Long-Lasting Effects in Rat Models of Posttraumatic Stress Disorder via a Novel Mechanism Associated with Structural Plasticity.
Posttraumatic stress disorder is an anxiety disorder characterized by deficits in the extinction of aversive memories. Insulin-like growth factor 1 (IGF1) is the only growth factor that has shown anxiolytic and antidepressant properties in human clinical trials. In animal studies, insulin-like growth factor binding protein 2 (IGFBP2) shows both IGF1-dependent and IGF1-independent pharmacological effects, and IGFBP2 expression is upregulated by rough-and-tumble play that induces resilience to stress.



IGFBP2 was evaluated in Porsolt, contextual fear conditioning, and chronic unpredictable stress models of posttraumatic stress disorder. The dependence of IGFBP2 effects on IGF1- and AMPA-receptor activation was tested using selective receptor antagonists. Dendritic spine morphology was measured in the dentate gyrus and the medial prefrontal cortex 24 hours after in vivo dosing.



IGFBP2 was 100 times more potent than IGF1 in the Porsolt test. Unlike IGF1, effects of IGFBP2 were not blocked by the IGF1-receptor antagonist JB1, or by the AMPA-receptor antagonist 2,3-Dioxo-6-nitro-1,2,3,4 tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX) in the Porsolt test. IGFBP2 (1 µg/kg) and IGF1 (100 µg/kg i.v.) each facilitated contextual fear extinction and consolidation. Using a chronic unpredictable stress paradigm, IGFBP2 reversed stress-induced effects in the Porsolt, novelty-induced hypophagia, sucrose preference, and ultrasonic vocalization assays. IGFBP2 also increased mature dendritic spine densities in the medial prefrontal cortex and hippocampus 24 hours postdosing.



These data suggest that IGFBP2 has therapeutic-like effects in multiple rat models of posttraumatic stress disorder via a novel IGF1 receptor-independent mechanism. These data also suggest that the long-lasting effects of IGFBP2 may be due to facilitation of structural plasticity at the dendritic spine level. IGFBP2 and mimetics may have therapeutic potential for the treatment of posttraumatic stress disorder.
Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, Northwestern University, Evanston, Illinois (Drs Burgdorf and Moskal); Aptinyx Inc., Evanston, Illinois (Dr Colechio, Ms Ghoreishi-Haack, and Drs Gross, Kroes, and Moskal); Afraxis Inc., La Jolla, California (Dr Rex); Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York (Drs Zhang and Stanton).
Jeffrey
J
Burgdorf
Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, Northwestern University, Evanston, Illinois (Drs Burgdorf and Moskal); Aptinyx Inc., Evanston, Illinois (Dr Colechio, Ms Ghoreishi-Haack, and Drs Gross, Kroes, and Moskal); Afraxis Inc., La Jolla, California (Dr Rex); Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York (Drs Zhang and Stanton).
Elizabeth M
EM
Colechio
Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, Northwestern University, Evanston, Illinois (Drs Burgdorf and Moskal); Aptinyx Inc., Evanston, Illinois (Dr Colechio, Ms Ghoreishi-Haack, and Drs Gross, Kroes, and Moskal); Afraxis Inc., La Jolla, California (Dr Rex); Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York (Drs Zhang and Stanton).
Nayereh
N
Ghoreishi-Haack
Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, Northwestern University, Evanston, Illinois (Drs Burgdorf and Moskal); Aptinyx Inc., Evanston, Illinois (Dr Colechio, Ms Ghoreishi-Haack, and Drs Gross, Kroes, and Moskal); Afraxis Inc., La Jolla, California (Dr Rex); Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York (Drs Zhang and Stanton).
Amanda L
AL
Gross
Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, Northwestern University, Evanston, Illinois (Drs Burgdorf and Moskal); Aptinyx Inc., Evanston, Illinois (Dr Colechio, Ms Ghoreishi-Haack, and Drs Gross, Kroes, and Moskal); Afraxis Inc., La Jolla, California (Dr Rex); Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York (Drs Zhang and Stanton).
Christopher S
CS
Rex
Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, Northwestern University, Evanston, Illinois (Drs Burgdorf and Moskal); Aptinyx Inc., Evanston, Illinois (Dr Colechio, Ms Ghoreishi-Haack, and Drs Gross, Kroes, and Moskal); Afraxis Inc., La Jolla, California (Dr Rex); Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York (Drs Zhang and Stanton).
Xiao-Lei
XL
Zhang
Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, Northwestern University, Evanston, Illinois (Drs Burgdorf and Moskal); Aptinyx Inc., Evanston, Illinois (Dr Colechio, Ms Ghoreishi-Haack, and Drs Gross, Kroes, and Moskal); Afraxis Inc., La Jolla, California (Dr Rex); Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York (Drs Zhang and Stanton).
Patric K
PK
Stanton
Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, Northwestern University, Evanston, Illinois (Drs Burgdorf and Moskal); Aptinyx Inc., Evanston, Illinois (Dr Colechio, Ms Ghoreishi-Haack, and Drs Gross, Kroes, and Moskal); Afraxis Inc., La Jolla, California (Dr Rex); Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York (Drs Zhang and Stanton).
Roger A
RA
Kroes
Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, Northwestern University, Evanston, Illinois (Drs Burgdorf and Moskal); Aptinyx Inc., Evanston, Illinois (Dr Colechio, Ms Ghoreishi-Haack, and Drs Gross, Kroes, and Moskal); Afraxis Inc., La Jolla, California (Dr Rex); Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York (Drs Zhang and Stanton).
Joseph R
JR
Moskal
D000818:Animals; D049229:Dendritic Spines / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018891:Dentate Gyrus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology; D005239:Fear / Q000187:drug effects / Q000502:physiology; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000008:administration & dosage / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000378:metabolism; D007858:Learning / Q000187:drug effects / Q000502:physiology; D008297:Male; D000069077:Memory Consolidation / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011619:Psychotropic Drugs / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D013313:Stress Disorders, Post-Traumatic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D018971:Insulin-Like Growth Factor Binding Protein 2; D011619:Psychotropic Drugs; D018091:Receptors, AMPA; C548904:insulin-like growth factor-1, rat; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1
dendritic spines; insulin-like growth factor I; insulin-like growth factor binding protein 2; posttraumatic stress disorder; resilience