Role of the Cholinergic System in Modulation of Tinnitus

Role of the Cholinergic System in Modulation of Tinnitus
James Kaltenbach, Ph.D., Cleveland Clinic, Cleveland, OH

Funding: $50,000

Roadmap to a Cure: Pathway C

Tinnitus is often attributed to hyperactivity of the brain’s auditory neurons. (Neurons are special cells that process sound information through electrical and chemical signals.) When a person is exposed to a loud sound or other tinnitus-inducing trauma, the brain circuits get altered and neurons start firing excessively. The result is the perception of sound when no external noise is present. In this model of tinnitus, the perception of sound (ringing) could be eliminated by reducing or compensating for the hyperactivity of these neurons.

Dr. Kaltenbach’s laboratory at the Cleveland Clinic has been studying the brain’s cholinergic system—how neurons transmit information using chemical neurotransmitters—and has identified a specific neurotransmitter, acetylcholine, that modulates the hyperactivity that underlies tinnitus. His previous research has already shown that the chemical compound Carbachol successfully activates the acetylcholine receptor, reducing neural hyperactivity and effectively eliminating tinnitus. Unfortunately, this compound is not useful as a therapy due to its extreme side effects, which include significant damage to the heart and gastrointestinal system.

However, Dr. Kaltenbach believes it is possible to identify a related compound that only targets neural activity related to tinnitus. (Each neuron has many receptor subtypes, each controlling a different neural reaction; the key to this study is finding a chemical compound that will stimulate only those receptors related to auditory activity.) Dr. Kaltenbach will use funding from ATA to explore three particularly promising compounds that target specific receptors in animals, to see which one best and most safely suppresses neuron hyperactivity and the perception of tinnitus. He is especially optimistic about work related to the muscarinic receptors, as there is already a strong consensus that drug interactions with these receptors are safe for humans.

The potential impact of this research is huge. If Dr. Kaltenbach can show that activating one or more receptor subtypes results in suppression of tinnitus, it would implicate these specific neural areas as useful drug targets. If successful, this research would accelerate the development of commercially-available prescription medications to silence tinnitus.

 

Hmmm, this seems to go against Prof. Tzounopoulus's paper Pathogenic plasticity of Kv7.2/3 channel activity is essential for the induction of tinnitus where he says:

KCNQ channels, often KCNQ2 and KCNQ3, mediate the native neuronal M-type current. M currents are strongly inhibited by activation of muscarinic acetylcholine receptors (mAChRs) and other G protein-coupled receptors that reduce membrane phosphatidylinositol-(4,5)-bisphosphate (PIP2) levels. Given the important role of cholinergic activity in DCN synaptic plasticity and that noise exposure increases cholinergic activity in the DCN, our results suggest that noise-induced up-regulation of mAChR signaling may underlie the reduced KCNQ channel activity in tinnitus mice.​

In other words according to this, the M currents of the Kv7+ channels (that Retigabine and similar drugs try to enhance) are actually inhibited (i.e. diminished) when acetylcholine receptors are activated. That is, their activation causes the problem, not the solution! What gives?

It seems the layout of what affects what is the following:

1) Hyperactivity in the fusiform cells in the DCN cause tinnitus.
2) Cartwheel cells exert a powerful inhibitory influence on fusiform cells.
3) 'Parallel fibers' (which are the axons of granule cells drive the cartwheel cells with excitatory inputs.
4) Major source of input to the granule cells system that drives cartwheel cells is from olivocochlear bundle which is largely cholinergic.

So we have: cholinergic (acetylcholine) influence on olivocochlear bundle → causes granule cells to send excitatory inputs on their axons (the parallel fibers) to cartwheel cells → causes cartwheel cells to exert an inhibitory influence on fusiform cells → reduces hyperactivity in the fusiform cells and stops tinnitus.

Now it could be that this cholinergic pathway (when acetylcholine is applied to olivocochlear bundle), suppresses tinnitus, but some other cholinergic pathway (when acetylcholine is applied elsewhere, perhaps directly to fusiform cells) increases tinnitus (by inhibiting M channels, like the Tzounopoulos paper description).

 

So since this thread started 9 years ago, there have been several experiments into the Muscarinic receptors in tinnitus generation.

There is this one by Dr. Shore et. al., in 2017:

Muscarinic acetylcholine receptors control baseline activity and Hebbian stimulus timing-dependent plasticity in fusiform cells of the dorsal cochlear nucleus

And this one by Prof. Malfatti et. al., in 2022:

Decreasing dorsal cochlear nucleus activity ameliorates noise-induced tinnitus perception in mice

Various agonists and antagonists used but I don't really understand the clinical implications of this.

 

A new study has been published on Muscarinic M1 receptors.

In Silico Study in MPO and Molecular Docking of the Synthetic Drynaran Analogues Against the Chronic Tinnitus: Modulation of the M1 Muscarinic Acetylcholine Receptor

@Uklawyer, @DebInAustralia, of interest?