Harnessing natural cellular variability to understand how neurons maintain their axodendritic polarity

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The different parts of your body all play different roles in keeping you alive and healthy. But dividing jobs between different spatial compartments like this doesn't just happen at the level of the whole organism - many of your individual cells do this too. This phenomenon of compartmentalising functions within distinct sub-cellular zones is known as 'polarity', and it reaches its peak in your brain cells, or neurons. Most neurons are broadly divided into two major polar specialisations: dendrites and axons. These have distinct structural and functional attributes that are crucial for information flow within neuronal circuits. Understanding how individual neurons organise themselves into axons and dendrites is therefore vital for understanding how a healthy brain operates. However, while we know a good amount about the processes involved in setting up neuronal polarity in the first place, we currently know a lot less about how neurons keep their polarity intact afterwards. How do neurons make sure that their axons stay axons, and their dendrites stay dendrites? Given that your brain cells are normally about as old as you are, maintaining polarity like this is a process that must operate successfully over decades. On the other hand, any deficits in polarity maintenance have the potential to fundamentally disrupt brain function.For these reasons, the goal of our proposal is to discover novel mechanisms that neurons use to maintain their polarity. We will do this by taking advantage of a unique case of natural variability. Whilst almost all mature neurons in the mammalian brain possess one, and only one axon, our laboratory has recently identified a population of cells that is very different. In the olfactory bulb, the first region of the brain to process information about the sense of smell, there is a set of neurons that naturally come in different polarity types. Some of these dopamine-releasing neurons possess an axon, but others lack an axon entirely. We will exploit this natural heterogeneity by using cutting-edge technology to compare and manipulate these different sub-types of dopaminergic cell at the molecular level. In doing so, we will ask which mechanisms are crucial for maintaining axons as axons and which are vital for maintaining dendrites as dendrites.By addressing these important basic biological questions, our proposal has the potential to positively impact future healthcare in the UK. Our study of the olfactory system could benefit future approaches to treat debilitating smell disorders such as anosmia and hyposmia, which affect at least 20% of the population and have a significant impact on quality of life. Our focus on dopaminergic neurons may inform treatments for disorders where these cells are lost in later life, such as Parkinson's Disease. Finally, any new knowledge we generate about ways to maintain the identity of neuronal compartments could prove crucial in therapeutic efforts to repair damage after brain injury or neurodegenerative disease.