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

MITSCHELEN M; YAN H; FARLEY JA; WARRINGTON JP; HAN S; HEREÑU C; CSISZAR A; UNGVARI Z; BAILEY-DOWNS LC; BASS CE; SONNTAG W.E.

NEUROSCIENCE

PERGAMON-ELSEVIER SCIENCE LTD

Año: 2011 vol. 30 p. 50 - 60

0306-4522

ABSTRACT Numerous studies support the hypothesis that insulin-like growth factor I (IGF-1) deficiency in adults may cause depression, but direct evidence is limited.  Many other psychological and pro-cognitive effects have been attributed to IGF-1, but appropriate animal models of adult-onset IGF-1 deficiency are lacking.  The need for such models is highlighted by the characteristic decline of IGF-1 in humans throughout adulthood.  Particularly in the geriatric population, IGF-1 levels are low and incidence of diminished mood and cognition is frequent.  IGF-1 levels in the brain are dependent both upon circulating IGF-1, produced primarily in the liver, and local production of IGF-1.  Therefore, models of adult-onset IGF-1 deficiency ideally should allow for separate characterization of these multiple sources to control for local compensation of generalized deficiency and vice versa.  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.  We demonstrate that adult-onset IGF-1 deficiency alone, in the absence of other endocrine or developmental abnormalities, is sufficient to cause a depressive phenotype in mice.  The knockouts do not cause detectable locomotor or anxiogenic phenotypes.  Furthermore, local compensation for deficiencies in circulating IGF-1 does not appear to occur in the hippocampus, nor are serum levels of IGF-1 upregulated in response to the moderate decline of hippocampal IGF-1 caused by the knockout in CA1.  Our results suggest that depression in a subset of the geriatric human population may be due exclusively to low IGF-1 levels in the brain, which are not ameliorated by local IGF-1 production or transport.