Abstract
Insulin-like growth factor 1 (IGF-1) signaling promotes brain development and plasticity. Altered IGF-1 expression has been associated to autism spectrum disorders (ASD). IGF-1 levels were found increased in the blood and decreased in the cerebrospinal fluid of ASD children. Accordingly, IGF-1 treatment can rescue behavioral deficits in mouse models of ASD, and IGF-1 trials have been proposed for ASD children. IGF-1 is mainly synthesized in the liver, and its synthesis is dependent on growth hormone (GH) produced in the pituitary gland. GH also modulates cognitive functions, and altered levels of GH have been detected in ASD patients. Here, we analyzed the expression of GH, IGF-1, their receptors, and regulatory hormones in the neuroendocrine system of adult male mice lacking the homeobox transcription factor Engrailed-2 (En2−/− mice). En2−/− mice display ASD-like behaviors (social interactions, defective spatial learning, increased seizure susceptibility) accompanied by relevant neuropathological changes (loss of cerebellar and forebrain inhibitory neurons). Recent studies showed that En2 modulates IGF-1 activity during postnatal cerebellar development. We found that GH mRNA expression was markedly deregulated throughout the neuroendocrine axis in En2−/− mice, as compared to wild-type controls. In mutant mice, GH mRNA levels were significantly increased in the pituitary gland, blood, and liver, whereas decreased levels were detected in the hippocampus. These changes were paralleled by decreased levels of GH protein in the hippocampus but not other tissues of En2−/− mice. IGF-1 mRNA was significantly up-regulated in the liver and down-regulated in the En2−/− hippocampus, but no differences were detected in the levels of IGF-1 protein between the two genotypes. Our data strengthen the notion that altered GH levels in the hippocampus may be involved in learning disabilities associated to ASD.
Highlights
Insulin-like growth factor 1 (IGF-1) is a hormone primarily produced by the liver, which exerts an endocrine action on multiple target tissues
Male mice from our colony. mRNA expression was studied in the hypothalamus, pituitary gland, and liver, as well as hippocampus and blood cell fraction
growth hormone (GH) mRNA was mainly detected in the pituitary gland, while much lower levels were present in the hippocampus, hypothalamus, liver, and blood (Figure 1B)
Summary
Insulin-like growth factor 1 (IGF-1) is a hormone primarily produced by the liver, which exerts an endocrine action on multiple target tissues. It is locally produced in tissues, including brain, where it acts in a paracrine/autocrine fashion. Several studies demonstrate that IGF-1 profoundly modulates brain function, both during development and adult life. [1]] and maturation of cortical and retinal function [2,3,4], whereas in adult life, it exerts multiple actions ranging from the control of synaptic plasticity to neuroprotection [reviewed in Ref. Altered levels of other hormones of the IGF-1 pathway have been associated to ASD [9]. GH modulates cognitive functions [16], and altered GH levels have been detected in ASD patients [17]
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