Momoko Takahashi, a Doctoral Student at Northwestern University, explains the complex research of neurotrophin signalling in the nervous system in this report
Ever since Rita Levi-Montalcini, Stanley Cohen, and Viktor Hamburger discovered the first neurotrophin over a half-century ago,(1,2) scientists have continuously worked on characterising this class of proteins, its receptors, and its signalling pathways. What has been revealed is that the complexity of neurotrophin actions are immense; not only do neurotrophins determine the fate of brain cells, known as neurons, they also regulate proliferation, survival, differentiation, migration and neuronal death3. Neurotrophins behave differently depending on their location in the nervous system, developmental time period, and species of animal,(4) acting on a multitude of key biological pathways and functions.(5)
Three primary neurotrophins and their corresponding receptors are known today. They are nerve growth factor (NGF) and its receptor, tyrosine receptor kinase A (TrkA), brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine receptor kinase B (TrkB), and neurotrophin-3 (NT-3) and its receptor, tyrosine receptor kinase C (TrkC).6–12 However, due to the lack of available pharmacological tools, as well as discovery order, the literature on the actions of NT-3/TrkC signalling is less when compared to the other neurotrophins.
The literature that does exist, however, tells a complex story regarding the function of NT-3/TrkC signalling. Research shows that TrkC induces cell death without NT-3 activation,4,13 implicating alternate signalling pathway that involves TrkC but not NT-3. Complicating matters more is the fact that TrkC also has multiple isoforms with each behaving differently.14 Despite these obstacles, recent research strongly suggests that NT-3/TrkC pathway deserves to be studied not only because of its biological, but also clinical significance, (15,16) especially in terms of neurological diseases and the advent of pluripotent stem cells. (17–20) In this research profile, we briefly describe areas of established research in the brain, as well as highlighting mechanisms of NT-3/TrkC signalling in the auditory system – an area of interest for our laboratory.
In the hippocampus, where neuronal plasticity is heavily dependent on neurogenesis and differentiation to integrate into neural networks,(21) the NT-3/TrkC signalling pathway plays an active role in maintaining network architecture. Learning and memory are reliant on this; animals that lack NT-3/TrkC signalling have deficits in memory tasks.(22) It was recently discovered that NT-3/TrkC also facilitates synaptogenesis by interacting with a molecule known as PTPσ.(23–27) This was a novel discovery because the classical model argues that Trk receptors interact only with neurotrophins.
At the cellular level, the story becomes more complex. Injecting NT-3 into hippocampus neurons permits signals to travel backwards from the axon to the cell body.(28) This phenomenon, called retrograde axonal transport, indicates a continued targeted effect in the cell body of neurons, a site where multiple survival-promoting effects are initiated. Not only does the NT-3/TrkC pathway promote axonal transport, but it also regulates the location of the axon initial segment, altering neuronal excitability and action potential dynamics.(29)
The cerebellum and Purkinje cells
In the cerebellum, the unique and large dendritic architecture of Purkinje cells shed an interesting light onto NT-3/TrkC signalling. With the genetic deletion of TrkC, elaborate dendritic arborisation of Purkinje cells is minimal; however, the fact that dendritic structure is not entirely eliminated suggests that NT-3/TrkC signalling plays another role in dendritic maintenance. Removal of endogenous NT-3 alleviated the reduction of dendritic arborisation, indicating that the NT-3/TrkC pathway controls the neighbouring neuron’s dendrite structure in order to maintain a particular density of dendritic architecture within this specific brain region.(30–32)
The auditory system
Several lines of research suggest that the auditory system is dependent on neurotrophin signalling for its proper function and the field of auditory neural science can yield a wealth of knowledge if delved further. Still, the study of NT-3/TrkC signalling in the auditory system can also be a complex endeavour, in part due to the topological gradients of TrkB and TrkC that coexist in same brain regions.
For example, the chicken auditory system shows an interesting developmental pattern that is reliant on both Trk receptors.8 However, a global genetic deletion of either protein can be fatal to the animal, and therefore, methods like the one reviewed in our previous research profile – e.g., focal gene manipulation via in ovo electroporation – must be used to further elucidate its functions (please see Open Access Government, January 2019 issue, pages 130-33).
In terms of auditory functions, NT-3/TrkC does several crucial things. It plays a role in regulating action potential properties of auditory neurons in the peripheral pathway;(33) our laboratory has discovered that this happens in the central system as well. Here, neurotrophin signalling regulates action potential kinetics by maintaining a balance between different types of potassium channels.(34) We suggest that this function is critical in establishing normal tonotopic gradients, a biological process required for the neural encoding of different sound frequencies.
Similarly, NT-3/TrkC signalling modifies potassium conductance of inner hair cells in guinea pigs, depressing responses and permitting repetitive action potential firing.(35) It also increases calcium currents in the chicken inner ear, promoting more efficient synaptic transmission(36) and in mice, it is involved in synaptic maintenance and neuronal migration of the auditory nerve.6
With respect to hearing, correct levels of NT-3/TrkC signalling is required to maintain inner ear health. For example, NT-3 induces synapse regeneration in the inner ear and can repair synapses after acoustic trauma in mice.15 Similarly, overexpressing NT-3 protects inner ear synapses by promoting its repair after noise-induced synaptopathy in guinea pigs.(37) Conversely, excessive levels of NT-3 in the inner ear can also disrupt the synaptic network of the same species and therefore, negatively affect hearing properties.(38) This suggests that the inner ear requires just the right amount of NT-3 in order for TrkC signalling to be effective in maintaining normal hearing health.
What does this all mean? Few things can be assumed from studies in both normal and abnormal NT-3/TrkC signalling. One conclusion is that due to its ubiquitous presence, a careful study of NT-3/TrkC temporal and spatial expression is necessary before embarking on clinical applications. Nevertheless, research studies in the brain and auditory system suggest that targeting the NT-3/TrkC pathway shows promise as a non-invasive and effective method to treat neurological and auditory ailments.
Momoko Takahashi1 and Jason Tait Sanchez(1,2,3)
1.)The Roxelyn and Richard Pepper Department of Communication Sciences and Disorders, 2.)Neurobiology Department, and 3The Hugh Knowles Hearing Research Center. Northwestern University. Evanston, Illinois, 60208, USA.
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34.) Hong, H., Takahashi, M. & Sanchez, J. T. Neurotrophic factors regulate functional properties in the developing auditory brainstem. ARO MWM Poster Abstract PS859. Baltimore, MD (2019).
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Jason Tait Sanchez, Ph.D., CCC-A, FAAA
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