Understanding the relationship between the perineuronal net and glia within the auditory pathway in a mouse model of age-related hearing loss

Abstract

Age-related hearing loss (ARHL) affects over 11 million people in the UK and ~50% of over 75yr olds. Although hearing loss is often perceived as an inconsequential part of aging, there is evidence it is important in general brain health. Adults with ARHL develop significant impairments in their cognitive abilities 3 years sooner and 30-40% more severely than those with normal hearing. The severity of ARHL is associated with a greater risk (2-5 fold) of developing dementia. Hearing aids and cochlear implants improve quality of life for many individuals however there are no approved therapies to prevent or slow ARHL. This is likely due to inadequate understanding of the neurobiological changes underling the progression of this chronic debilitating condition. In a murine model of ARHL, we have observed changes within the auditory pathway in both the perineuronal net (PNN) and glia.We hypothesise that the loss of sensory input to the auditory nerve in ARHL may induce compensatory changes to the PNN to alter neuronal activity and synaptic plasticity. Such changes may contribute to a pathological glial response making the auditory pathway more vulnerable to inflammation and progression of hearing loss.The auditory circuit is modulated by synaptic inhibition to maintain temporal precision and process sound localization cues. The majority of fast-spiking interneurons associated with this inhibition are surrounded by a specialized extracellular matrix, the PNN. The PNN is important for synaptic stabilization, protects against glial activation and pathological insults and has restrictive effects on plasticity in the mature CNS.Here we exploit the well-characterized C57BL/6J mouse model of ARHL, to assess changes in expression and localization of the PNN and glial cells across the life-course and in disease progression. We have found changes in expression of the PNN during progression of hearing loss. We also observe changes in the organization and phenotype of microglia and astrocytes in the auditory pathway.Gaining a better understanding of the pathological processes involved in progression of ARHL may identify cellular or molecular compartments amenable to modulation. For example tempering the glial response and associated changes in the PNN may slow disease progression and help retain auditory function for longer. ARHL is associated with increased risk of developing dementia and exacerbating cognitive decline. Therapies that modulate ARHL could therefore be significant in the treatment of dementia and related neurodegenerative conditions