Matrix Metalloproteinases in the Degeneration of Cochlear Synapses
Abstract
Hearing loss, tinnitus, and other hearing dysfunctions are the most common injuries sustained by our armed services personnel. Service men and women are often exposed to loud noise and are at a significantly higher risk of sustaining concussions or other head trauma. These events can cause the nerve cells in the ear to detach from the sound-sensing cells, not unlike an electrical cord being ripped from the socket. This injury is called cochlear synaptopathy and it can lead to several problems: (1) difficulty hearing in noisy environments, (2) ringing in the ears (tinnitus), (3) hearing loss, (4) difficulty in attention and learning, and other forms of hearing dysfunction. These hearing deficits adversely affect soldierly performance and negatively impact survival and quality of life for armed services members. What s more, these same issues can and do afflict many members of the general public who have been exposed to too much loud noise or who have sustained a concussion or other head injury. Currently, preventative or restorative treatments are lacking. This is due in part to the fact that the biological underpinnings of cochlear synaptopathy are not well understood. Here, we propose a novel mechanism for cochlear synaptopathy that involves structures called perineuronal nets (PNNs), which normally act like a scaffold to hold the ends of the nerve cell fibers in place. We hypothize that these scaffolds get degraded, or are torn down, by a class of enzymes called matrix metalloproteinases (MMPs). Here we show preliminary data that PNNs in the inner ear do appear to be degraded by noise or by concussion-like injuries. We also show that matrix metalloproteinase 9 (MMP9), an enzyme known to degrade PNNs, is upregulated following noise exposure and following a head injury. Thus we hypothesize that noise or head injury can cause MMP9 upregulation, which causes PNN degradation, which leads to cochlear synaptopathy. We further speculate that treatments that inhibit the MMP enzymes can prevent PNN degradation, preserve the synaptic connections, and thus reduce or prevent hearing dysfunction that results from cochlear synaptopathy. This proposal therefore seeks to test the extent to which noise or concussion degrades cochlear PNNs by investigating multiple proteins that make up PNNs and by looking at these proteins at multiple timepoints after noise exposure or concussion. This proposal also seeks to determine whether inhibition of MMPs can prevent the disconnecting of auditory nerve fibers and thus prevent the hearing problems that arise from noise or concussion. To do this, we will test several drugs that can inhibit MMP activity and see if, in response to any of these treatments, the nerve fibers can remain connected to the sensory cells of the inner ear and normal hearing can be preserved. The potential impact of these studies is great. First, they will significantly advance our basic biological understanding of cochlear synaptopathy by demonstrating a novel mechanism and potential therapeutic target for treating noise-induced hearing dysfunction. Second, we will directly test MMP inhibitors for their ability to mitigate or prevent synaptopathy, and, if successful, this could lead to the use of these or similar drugs to prevent or treat cochlear synaptopathy in clinical settings. Thus, these experiments hold the potential to prevent or mitigate hearing loss or other hearing dysfunction in Service members and in the population at large, both of which have high incidences of concussions and exposures to loud noise.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010772
Entities
People
- Bradley J Walters
Organizations
- United States Army
- University of Mississippi Medical Center