Neurogenetics of Auditory Function

Research in the Tempel lab is aimed at understanding various components of the complex biological process of hearing, both in the cochlea where sounds are transduced by hair cells and in the central nervous system where sounds are encoded by action potentials transmitted to the auditory cortex. We use the power of genetics to unravel this complexity, leaping from behavior to molecules by studying deaf mouse mutants and human families with heritable forms of hearing loss. These “patients” allow us to identify specific genes contributing to the process of hearing. Detailed studies on each gene provide us with information on how hearing happens and how it might be ameliorated in people with hearing loss.

Genetics of Hearing Loss

Approximately one in every thousand babies is born with significant hearing loss; at least half of these cases are due to an inherited genetic condition. As people age, noise-induced and/or age-related hearing loss causes significant hearing loss and interferes with speech communication in roughly 50% of the U.S. population at retirement age. The effects of hearing loss have both economic and interpersonal consequences for affected individuals and their families.

In 1998 we discovered that the deafwaddler mouse was deaf because of a mutation in a calcium ion pump, PMCA2 (Street et al., 1998). Recent work has shown that even slight reductions in activity of this pump causes high frequency hearing loss in mice that is very similar to age-related hearing loss, or presbycusis, in humans (McCullough and Tempel, 2004). Ongoing studies are aimed at identifying ways to prevent hearing loss in deafwaddler mice using pharmacological or gene-therapy approaches.

In collaboration with colleagues at Harvard University, we are analyzing strains of mice that are uniquely resistant to noise exposure. We use quantitative trait locus (QTL) mapping techniques to identify chromosomal regions that make these mice resistant to noise. We also use DNA micro-array techniques to identify genes that are differentially expressed between resistant and non-resistant strains of mice. Genes that are differentially expressed AND map to the QTL regions are particularly good candidates for further studies. Homologous genes in humans are likely to contribute to noise resistance in man.

Auditory Signal Encoding

The ability to localize the source, intensity and pitch of a sound is critical for locating predators, enjoying music and having a casual conversation. These higher order auditory functions require that sounds be encoded by the nervous system and transmitted as action potentials with high temporal precision and fidelity. Similar requirements for rapid, precise temporal encoding are needed for fine muscle control in the descending motor pathway. To meet these demands, the nervous system has developed a number of specializations including the use of specific voltage-gated potassium channels that open quickly and prevent extra action potentials that would degrade the encoded information. These channels are localized to specific parts of the neurons where action potential are initiated and propagated. We have studied two of these genes – Kv1.1 and Kv1.2 – by making knockout mice that lack each of the genes and then analyzing the effect on behavior and transmission. We find that deletion of either of these two genes causes epilepsy in the knockout mice. When studied using electrophysiology, action potential transmission is altered in auditory nuclei of mice lacking Kv1.1, whether in tissue slices (Brew et al., 2003) or in vivo (Kopp-Scheinpflug et al., 2003).

We reported in 2001 that deafness in quivering mice was caused by mutations in a structural gene, spectrin beta 4, which anchors sodium channels at axon initial segments and at nodes of Ranvier (Parkinson et al., 2001). We hypothesize that action potential transmission is again altered in auditory nuclei but in this mutant because the balance between excitatory sodium channels and inhibitory potassium channels is disrupted. Ongoing studies on an allelic series of quivering mice are aimed at identifying the critical sites of action for the spectrin beta 4 gene.

In summary, studies in our lab use genetics as a starting point. That each of the mutant mouse strains (or human families) have a phenotype tells us that the altered gene is important. The complex structure of the auditory system and it’s demand for fast and precise encoding is the likely reason why there are a large number of genes, mutation of which causes hearing loss. The fact that auditory malfunctions are not lethal to the organism makes genetic analysis of hearing loss a particularly useful way to probe the biological basis of this elegantly evolved sensory system.