Long-term deficiency of circulating and hippocampal insulin-like growth factor I induces depressive behavior in adult mice: a potential model of geriatric depression

Abstract

Numerous studies support the hypothesis that deficiency of insulin-like growth factor I (IGF-1) in adults contributes to depression, but direct evidence is limited. Many psychological and pro-cognitive effects have been attributed to IGF-1, but appropriate animal models of adult-onset IGF-1 deficiency are lacking. In this study, we use a viral-mediated Cre-loxP system to knockout the Igf1 gene in either the liver, neurons of the CA1 region of the hippocampus, or both. Knockout of liver Igf1 reduced serum IGF-1 levels by 40% and hippocampal IGF-1 levels by 26%. Knockout of Igf1 in CA1 reduced hippocampal IGF-1 levels by 13%. The most severe reduction in hippocampal IGF-1 occurred in the group with knockouts in both liver and CA1 (36% reduction), and was associated with a 3.5-fold increase in immobility in the forced swim test. Reduction of either circulating or hippocampal IGF-1 levels did not alter anxiety measured in an open field and elevated plus maze, nor locomotion in the open field. Furthermore, local compensation for deficiencies in circulating IGF-1 did not occur in the hippocampus, nor were serum levels of IGF-1 upregulated in response to the moderate decline of hippocampal IGF-1 caused by the knockouts in CA1. We conclude that adult-onset IGF-1 deficiency alone is sufficient to induce a depressive phenotype in mice. Furthermore, our results suggest that individuals with low brain levels of IGF-1 are at increased risk for depression and these behavioral effects are not ameliorated by increased local IGF-1 production or transport. Our study supports the hypothesis that the natural IGF-1 decline in aging humans may contribute to geriatric depression.

Serum insulin-like growth factor 1 and late-life depression: A population-based study

“…This is in contrast with studies using animal models or adult patients with GHD (i.e. pathological GHD due to hypothalamic or pituitary defects) that did find supportive evidence for an association between the GH-IGF-1 axis and depression (Duman et al, 2009;Giusti et al, 1998;Kokshoorn et al, 2011;Mahajan et al, 2004;Mitschelen et al, 2011). Possibly, a longitudinal effect of IGF-1 on mood may only be present in a severe IGF-1 deficient state, during which other mechanisms may be involved than during the 'somatopause'.…”

“…GH supplementation has been shown to improve these symptoms (Kokshoorn et al, 2011;Mahajan et al, 2004). Since features of normal aging resemble those of GHD, it has been suggested that the 'somatopause' contributes to age-associated changes and disorders (Bartke, 2008;Corpas et al, 1993;Mahajan et al, 2004;Mitschelen et al, 2011). For instance, lower IGF-1 concentrations are related to impaired cognitive functioning, which frequently coincides with late-life depression, in healthy elderly (Arwert et al, 2005).…”

“…Also, there is evidence that IGF-1 has direct effects on the central nervous system (CNS) through blood-brain barrier passage and local autocrine and paracrine mechanisms (Schneider et al, 2003). Moreover, basic research has shown that the expression of neurotrophic and growth factors, such as IGF-1, is decreased by chronic stress and depression in brain regions associated with depression, and increased by antidepressant treatment (Duman, 2004;Mitschelen et al, 2011). Recently, an animal study demonstrated that adult-onset long-term IGF-1 deficiency is able to induce depressive behavior in normally developed mice (Mitschelen et al, 2011).…”

“…Moreover, basic research has shown that the expression of neurotrophic and growth factors, such as IGF-1, is decreased by chronic stress and depression in brain regions associated with depression, and increased by antidepressant treatment (Duman, 2004;Mitschelen et al, 2011). Recently, an animal study demonstrated that adult-onset long-term IGF-1 deficiency is able to induce depressive behavior in normally developed mice (Mitschelen et al, 2011). Nevertheless, only few studies with limited sample sizes and no or short follow-up time have addressed the relation between IGF-1 and depression in humans (Deuschle et al, 1997;Franz et al, 1999;Lesch et al, 1988aLesch et al, , 1988bRupprecht et al, 1989;Schilling et al, 2011;Weber-Hamann et al, 2009).…”

The impact of prenatal stress on insulin-like growth factor-1 and pro-inflammatory cytokine expression in the brains of adult male rats: The possible role of suppressors of cytokine signaling proteins

“…Both neurons and glial cells express IGF-1, which impacts the developing brain by modulating neural cell signaling and proliferation and by exerting multifunctional actions on the differentiation of progenitor neuronal cells, particularly in the hippocampus of adult rats (Trejo et al, 2001). Deficits in both central and peripheral IGF-1 levels may contribute to the development of affective disorders in humans and lead to the progression of depression-like symptoms in animals (Mitschelen et al, 2011). Furthermore, IGF-1 displays antidepressant-like properties: intracerebroventricular administration of IGF-1 reverses lipopolysaccharide (LPS)-evoked depression-like behavior in rodents (Park et al, 2011).…”