Abstract
Insulin-like growth factor 1 (IGF-1) is a powerful regulator of synaptic activity and a deficit in this protein has a profound impact on neurotransmission, mostly on excitatory synapses in both the developing and mature auditory system. Adult Igf1−/− mice are animal models for the study of human syndromic deafness; they show altered cochlear projection patterns into abnormally developed auditory neurons along with impaired glutamate uptake in the cochlear nuclei, phenomena that probably reflect disruptions in neuronal circuits. To determine the cellular mechanisms that might be involved in regulating excitatory synaptic plasticity in 4-month-old Igf1−/− mice, modifications to neuroglia, astroglial glutamate transporters (GLTs) and metabotropic glutamate receptors (mGluRs) were assessed in the cochlear nuclei. The Igf1−/− mice show significant decreases in IBA1 (an ionized calcium-binding adapter) and glial fibrillary acidic protein (GFAP) mRNA expression and protein accumulation, as well as dampened mGluR expression in conjunction with enhanced glutamate transporter 1 (GLT1) expression. By contrast, no differences were observed in the expression of glutamate aspartate transporter (GLAST) between these Igf1−/− mice and their heterozygous or wildtype littermates. These observations suggest that congenital IGF-1 deficiency may lead to alterations in microglia and astrocytes, an upregulation of GLT1, and the downregulation of groups I, II and III mGluRs. Understanding the molecular, biochemical and morphological mechanisms underlying neuronal plasticity in a mouse model of hearing deficits will give us insight into new therapeutic strategies that could help to maintain or even improve residual hearing when human deafness is related to IGF-1 deficiency.
Highlights
Gene knockout studies in mice have demonstrated that insulin-like growth factor 1 (IGF-1), a growth promoting hormone, is essential for the proper functioning of the inner ear (Magariños et al, 2012; Varela-Nieto et al, 2013; Yamahara et al, 2015)
Mice had shorter processes, which covered a smaller surface area than in Igf1+/+ and Igf1+/− mice. These observations were corroborated by analyses of variance (ANOVA), which demonstrated a significant effect of IGF-1 deficiency over the mean gray levels of ionized calcium-binding adaptor 1 (IBA1) immunostaining in the dorsal cochlear nucleus (DCN) (F(2,22) = 10.35, p < 0.001), posteroventral cochlear nucleus (PVCN) (F(2,15) = 13.86, p < 0.001) and anteroventral cochlear nucleus (AVCN) (F(2,18) = 13.81, p < 0.001), as well as over the immunostained areas in the DCN (F(2,22) = 10.77, p < 0.001), PVCN (F(2,15) = 9.94, p < 0.01) and AVCN (F(2,18) = 12.15, p < 0.001)
Further analysis using a Scheffé’s post hoc test determined that the mean gray levels in the Igf1−/− mice were significantly lower than in the Igf1+/+ (p < 0.01 for the DCN, p < 0.001 for the PVCN and AVCN) and Igf1+/− (p < 0.05 for the DCN and AVCN, p < 0.01 for the PVCN) mice (Figures 2I, 4)
Summary
Gene knockout studies in mice have demonstrated that insulin-like growth factor 1 (IGF-1), a growth promoting hormone, is essential for the proper functioning of the inner ear (Magariños et al, 2012; Varela-Nieto et al, 2013; Yamahara et al, 2015). The lack of IGF-1 modifies excitatory but not inhibitory synapses in the cochlear nuclei, evident as an upregulation in the vesicular glutamate-transporter 1 (VGluT1; Fuentes-Santamaría et al, 2016). This modulation involves myocyte enhancer factor-2 (MEF2) transcription factors, which are downregulated in the IGF-1-deficient cochlea and cochlear nucleus, and that play a pivotal role in regulating excitatory synapses (Flavell et al, 2006; Ruffle et al, 2006; Sanchez-Calderon et al, 2010; Rashid et al, 2014)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
