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Our laboratory studies the generation and propagation of neural signals in the inner ear. We use biophysical, electrophysiological, molecular biological and histological methods to determine fundamental molecular mechanisms by which neurotransmitters are released from primary sensory cells (‘hair cells’) to excite second order neurons carrying information to the brain. We apply these same techniques to study inhibitory feedback produced by brain neurons that project to and regulate the sensitivity of the cochlea.
Our studies concentrate on the properties of voltage and/or ligand-gated ion channels and transporters expressed in hair cells, neurons and supporting cells of the cochlea. Ion channels, neurotransmitter receptors and transporters are therapeutic targets for the treatment of virtually all diseases of the nervous system.
Discoveries from this laboratory will help advance therapeutic approaches to hearing loss by identifying these essential molecules and defining their functional roles in the cochlea.
Recent Findings
Sounds in the world around us are converted into neuro-electrical signals in the inner ear, or cochlea. Mechanosensory ‘hair cells’ generate tiny voltage changes depending on the intensity and frequency composition of a sound wave. That initial voltage signal is communicated to a second order neuron through the release of chemical neurotransmitters. Neurotransmitter release is dependent on calcium influx through a specialized class of voltage-gated ion channels in hair cells related to those targeted in some forms of cardiovascular disease. Voltage- and ligand-gated potassium channels interact with the calcium channels to establish the overall response dynamics. We have generated basic information about the identity and regulated expression of the genes encoding calcium and potassium channels in hair cells.
Martinez-Dunst, C., R. Michaels and P.A. Fuchs (1997). Release sites and calcium channels in hair cells of the chick's cochlea. Journal of Neuroscience 17:9133-9144.
Ramanathan, K., T. Michael, G-J. Jiang, H. Hiel and P.A. Fuchs (1999). A molecular mechanism for the electrical tuning of cochlear hair cells. Science. 283:215-217.
Duncan R.K. and P.A. Fuchs (2003) Tonotopic variation in the properties of large-conductance, calcium-activated potassium channels in hair cells along the chick basilar papilla. Journal of Physiology (London) 547:357-71.
Release of neurotransmitter from mechanosensory hair cells occurs at specialized structures called dense bodies or ribbons (by analogy to similar connections in the retina).
Neurotransmitter (probably the amino acid glutamate) comes prepackaged in small vesicles whose contents are released by the ribbon synapse. The released glutamate then activates specific receptor/ion channels to excite the postsynaptic afferent neuron. Our studies have confirmed the functional character of these glutamate receptors, and added new information about the protein transporters that re-sequester the glutamate to prevent over-excitation. We have also discovered that each ribbon synapse appears to release many vesicles at once, probably to ensure accurate timing required for sound localization.
Glowatzki E and PA Fuchs (2000). Cholinergic synaptic inhibition of inner hair cells in the neonatal mammalian cochlea. Science 288:2366-2368.
Glowatzki E and PA Fuchs (2002) Transmitter release at the hair cell ribbon synapse. Nature Neuroscience 5(2):147-154.
In addition to sending information to the brain, the inner ear is subject to feedback regulation from the brain. Neurons in the superior olivary complex of the brainstem send axons out to the cochlea where they release the neurotransmitter acetylcholine to inhibit mechanosensory hair cells. By recording from individual hair cells during this inhibitory process, we have shown that their acetylcholine receptors are related to the nicotinic receptors found in skeletal muscle, but with quite unusual pharmacology. Surprisingly, while acetylcholine excites skeletal muscle via its nicotinic receptors, hair cells are inhibited by theirs. Calcium ions play a central role in nicotinic inhibition, serving as a second messenger to activate potassium channels that hyperpolarize the hair cell. The molecular mechanisms underlying these native inhibitory processes may provide candidate approaches for therapeutic intervention.
Fuchs, P.A. and B.W. Murrow (1992a). Cholinergic inhibition of short (outer) hair cells of the chick's cochlea. Journal of Neuroscience. 12(3):800-809.
Hiel, H, Luebke AL and P.A. Fuchs (2000). Cloning and localization of the nicotinic subunit a9 in cochlear hair cells of the chick. Brain Research 858:215-225.
Lustig LL, Peng H, Hiel H, Yamamoto T and PA Fuchs (2001). Molecular cloning and mapping of the human nicotinic acetylcholine receptor a10 (CHRNA 10). Genomics 73(3):272-83.
Director of The Cochlear Neurotransmission Laboratory
Paul A. Fuchs, Ph.D. Professor, Otolaryngology- Head and Neck Surgery
