Project No. 2173

Primary Supervisor

Dr Katrin Deinhardt- University of Southampton

Co-Supervisor(s)

Prof Majid Hafezparast – University of Sussex

Dr Mariana Vargas-Caballero – University of Southampton

Summary

The formation and maintenance of the central nervous system throughout life is a tightly regulated process that is essential for cognitive function. Imbalances, such as excessive or limited connectivity, lead to neurodevelopmental disorders including autism spectrum disorders and schizophrenia.

In order to build and maintain individual neurons with their complex architecture, efficient material and information shuttling across distances is required. This intracellular transport relies on motor proteins and plays an essential role in axonal outgrowth and wiring during early development. We have previously shown that a point mutation in the motor protein dynein impairs axonal growth and arborisation. Moreover, we found that the neurotrophin BDNF promotes axonal branching by directly signalling to microtubules and altering their dynamics. We hypothesise that BDNF-driven axonal arborisation and synaptic strengthening require dynein function. To test this hypothesis, the student will investigate how BDNF and the microtubule-based motor dynein interact to promote axonal arborisation and synaptic connectivity. They will use primary neuronal cultures to assess microtubule dynamics by live cell imaging of cytoskeletal components, the efficiency and directionality of motor-based transport using fluorescent cargoes, and synaptic connectivity using pre- and postsynaptic markers. This will be complemented by patch-clamp electrophysiology to measure the strength of connectivity. Our previous work further demonstrated that the BDNF-MKP1-microtubule signalling pathway regulates arborisation of layer 2/3 cortical pyramidal neurons in vivo. To assess the role of dynein in this process and its impact on the wiring of cortical circuits, the student will prepare slices from wildtype and dynein mutant mice to measure the effect of BDNF on synaptic transmission using patch-clamp recordings, complemented by fluorescence microscopy to assess morphology.

A better understanding of the crosstalk between molecular motors and neurotrophic factors will provide a framework for studying the molecular mechanisms of innervation and axonal remodelling under normal and pathological conditions.