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GH Dysfunction in Engrailed-2 Knockout Mice, a Model for Autism Spectrum Disorders.

Giovanni Provenzano1, Elena Clementi1, Sacha Genovesi1

  • 1Laboratory of Molecular Neuropathology, Centre for Integrative Biology (CIBIO), University of Trento , Trento , Italy.

Frontiers in Pediatrics
|September 17, 2014
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Summary

Altered growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels in the hippocampus of En2 (-/-) mice may contribute to autism spectrum disorder (ASD) related learning disabilities.

Keywords:
autism spectrum disordersgrowth hormonehippocampusinsulin-like growth factorlivermouse modelneuroendocrine axispituitary gland

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Area of Science:

  • Neuroendocrinology
  • Developmental Neuroscience
  • Autism Spectrum Disorders Research

Background:

  • Insulin-like growth factor 1 (IGF-1) signaling is crucial for brain development and plasticity, with altered IGF-1 levels implicated in autism spectrum disorders (ASD).
  • Growth hormone (GH) also influences cognitive functions, and its dysregulation has been observed in ASD patients.
  • The homeobox transcription factor Engrailed-2 (En2) plays a role in neurodevelopment, and its absence (En2 (-/-)) leads to ASD-like behaviors and neuropathological changes.

Purpose of the Study:

  • To investigate the expression of GH, IGF-1, their receptors, and regulatory hormones in the neuroendocrine system of adult male En2 (-/-) mice, which exhibit ASD-like behaviors.
  • To explore the relationship between En2 deficiency, neuroendocrine alterations, and the neuropathological changes observed in these mice.

Main Methods:

  • Analysis of messenger RNA (mRNA) and protein expression levels of GH and IGF-1 in various tissues, including the pituitary gland, liver, hippocampus, and blood of En2 (-/-) mice and wild-type controls.
  • Assessment of ASD-like behaviors and neuropathological changes in En2 (-/-) mice.

Main Results:

  • En2 (-/-) mice showed significantly increased GH mRNA in the pituitary, blood, and liver, but decreased levels in the hippocampus compared to controls.
  • GH protein levels were reduced in the hippocampus of En2 (-/-) mice.
  • IGF-1 mRNA was upregulated in the liver and downregulated in the hippocampus of En2 (-/-) mice, with no significant differences in IGF-1 protein levels.
  • En2 (-/-) mice exhibited ASD-like behaviors, including social interaction deficits and impaired spatial learning.

Conclusions:

  • The study highlights significant deregulation of the GH axis in the neuroendocrine system of En2 (-/-) mice.
  • Altered GH levels specifically within the hippocampus may be a key factor contributing to the learning disabilities observed in this mouse model of ASD.
  • These findings suggest a potential role for hippocampal GH in the pathophysiology of learning impairments associated with autism spectrum disorders.