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.