Delayed Inner Ear Maturation and Neuronal Loss in PostnatalIgf-1-Deficient Mice

Abstract

Insulin-like growth factor-1 (IGF-1) has been shown to play a key role during embryonic and postnatal development of the CNS, but its effect on a sensory organ has not been studied in vivo. Therefore, we examined cochlear growth, differentiation, and maturation in Igf-1 gene knock-out mice at postnatal days 5 (P5), P8, and P20 by using stereological methods and immunohistochemistry. Mutant mice showed reduction in size of the cochlea and cochlear ganglion. An immature tectorial membrane and a significant decrease in the number and size of auditory neurons were also evident at P20. IGF-1-deficient cochlear neurons showed increased caspase-3-mediated apoptosis, along with aberrant expression of the early neural markers nestin and Islet 1/2. Cochlear ganglion and fibers innervating the sensory cells of the organ of Corti presented decreased levels of neurofilament and myelin P(0) in P20 mouse mutants. In addition, an abnormal synaptophysin expression in the somata of cochlear ganglion neurons and sensory hair cells suggested the persistence of an immature pattern of synapses distribution in the organ of Corti of these animals. These results demonstrate that lack of IGF-1 in mice severely affects postnatal survival, differentiation, and maturation of the cochlear ganglion cells and causes abnormal innervation of the sensory cells in the organ of Corti.

Genetic disorders in the GH–IGF-I axis in mouse and man

“…The delayed response to acoustic stimuli along the auditory pathway indicates the contribution of the CNS to the hearing loss in IGF-I deficiency (81). At a cellular level, a significant decrease in number and size of auditory neurons, increased apoptosis of cochlear neurons, a significant reduced volume of the cochlea and cochlear ganglion can result in abnormal differentiation and maturation of the cochlear ganglion cells and abnormal innervation of the sensory cells in the organ of Corti (82).…”

The Effect of Prenatal Stress on Auditory Brainstem Responses in Rat Pups

“…This could be due to the fact that stress affects various parts of CANS differently (11). It was highlighted in one study that the effect of stress on neuronal atrophy of inferior colliculus (IC) is much more than on the hippocampus (10). It was also revealed that after stress is induced to rats, expression of genes related to glucocorticoid receptor (GR) and Hif-1 (hypoxia-inducible factors) mainly occurs in IC and cochlear nuclei (11).…”

“…It was also revealed that after stress is induced to rats, expression of genes related to glucocorticoid receptor (GR) and Hif-1 (hypoxia-inducible factors) mainly occurs in IC and cochlear nuclei (11). This in indicative of the fact that unlike more peripheral structures, central parts of the afferent auditory pathway are more affected by prenatal stress (10). Since waves II and IV in rats are respectively generated by cochlear nuclei and IC (20), their increased latency time could be caused by greater impact of prenatal stress on their generators.…”

“…Animals with a history of stress over the fetal period also show greater involvement of the afferent auditory pathways (7). Of other consequences of fetal stress, impaired sensory gating (8), severe startle reflex (9), dendritic atrophy of auditory cortex (10), atrophy of auditory neurons in IC (11), and neuronal morphology defects in different parts of the central auditory nervous system (CANS) (11) can be mentioned. It was also reported that stress can impair cochlear function on the molecular level (11), which results in sudden hearing loss (SHL) (12), tinnitus and dizziness (13), and hyperacusis (11).…”

“…Through blocking growth factors, such as insulin-like growth factor 1 (IGF-1) (14) and increased activity of the HPA axis (5), stress changes the patterns of gene expression and causes the body to produce and store energy materials and increase cardiovascular activities, which often reduce fetal weight gain (14). Furthermore, IGF-1 is a powerful mitogen so when it is reduced, body's ability to maximize the speed of cell cycle during development is disrupted, which is followed by lower number of auditory sensory cells and auditory neurons (10). This issue has increased the prevalence of sensorineural hearing loss (SNHL) in people with lower birth weight (14).…”