IGFBP2 Produces Rapid-Acting and Long-Lasting Effects in Rat Models of Posttraumatic Stress Disorder via a Novel Mechanism Associated with Structural Plasticity

Abstract

Background: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.Methods: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.Results: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.Conclusions: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.

IGFBP2 Plays an Essential Role in Cognitive Development during Early Life

“…The relationship between stress and synaptic plasticity takes the form of an inverted-U, and the hippocampus is necessary for the enhancement and impairment of learning after stress. [31] Microarray analysis showed markedly increased-IGFBP2 mRNA in α-secretase cleaved amyloid precursor protein (a neuroprotective)-treated organotypic hippocampus slice culture. Persistent increases in SPAR expression as well as LTP were reported in mice exposed to intermittent hypoxia in a previous study from our lab.…”

IGFBP-2 Signaling in the Brain: From Brain Development to Higher Order Brain Functions

“…In adult male rats, IGFBP-2 (1 μg/kg, i.v.) increased the density of mature dendritic spines and total spine density in the DG and medial prefrontal cortex, which is the underlying mechanisms explaining the therapeutic-like effects of IGFBP-2 in post-traumatic stress disorder (PTSD) (126). In most cases, depressive symptoms associated with PTSD (127).…”

“…It has already been reported that insulin-like peptide plays an important role in neurite outgrowth (1). Moreover, IGFBP-2 increased total spines number in dentate granule neurons of the hippocampus and mature spine density in medial prefrontal cortex (MPFC) layer-V pyramidal neurons (126). Thus, IGFBP-2 may involve in increasing the number of functional synapses which can be the underlying mechanism of enhanced LTP by IGFBP-2.…”

Impacts of Psychological Stress on Osteoporosis: Clinical Implications and Treatment Interactions

“…Together, these studies suggest IGF as a potential connecting pathway between osteoporosis and psychological stress. Additional studies are needed to delineate the role of IGF-1 vs. IGF-2 and to determine how IGFBPs (64) may be temporally and differentially regulated during osteoporosis, psychological stress, and in osteoporotic patients who have a history of mental health disorders.…”