Cellular and molecular mechanisms regulating neuronal architecture and function : insights into the healthy and diseased brain

Brain derived neurotrophic factor (BDNF) is essential for the development and maintenance of neuronal architecture, activity and function and for mediating structural and functional plasticity. Several CNS disorders display BDNF deficiency, that correlates with disease severity and progression at the clinical level, poor cognitive performance and intellectual disability at the behavioral level and compromised neuronal structure and function at the cellular level. The first part of my thesis investigates the effects of Fingolimod- a well-tolerated pharmacological agent that augments endogenous BDNF levels, on neuronal architecture and activity in mature primary hippocampal cultures. Thereafter, I probed whether the positive structural alterations exerted by Fingolimod in healthy neurons could rescue cellular deficits in disorders that exhibit BDNF dysfunction - Alzheimer’s disease (AD), Rett syndrome (RTT) and Cdkl5 deficiency disorder (CDD).
In the second part of this thesis I investigated the mechanism of action of amyloid-β (Aβ) oligomers in determining the synaptotoxicity often associated with early cognitive decline in AD. The pan neurotrophin receptor (p75NTR) mainly known for its pro-apoptotic signaling, upon interaction with sub-lethal oligomeric Aβ concentrations, was found to induce dendritic spine loss and aberrant spine morphologies in primary hippocampal neurons. Using a combination of biochemical, imaging and pharmacological experiments, I here show that p75NTR-Aβ binding rapidly initiates restructuring of the underlying actin spinoskeleton by activating the Rho/ROCK signaling cascade.
The third part of my work is built around the exciting concept of hemispheric asymmetry. Although brain asymmetry is recognized for physiological processes like handedness, language processing etc., its existence in CNS disorders is rather under-explored, even though it manifests in progressive neurodegenerative disorders like AD. With CDD as my research model, I investigated whether neurodevelopmental disorders associated with intellectual disability could also display asymmetry, specifically in the bilateral hippocampus - the hub of learning and memory. Indeed, electrophysiological recordings from hippocampal slices of a CDD mouse model presented a leftward asymmetry in alterations of long term potentiation – the neural correlate of learning and memory. However, the basis of this asymmetry remains unknown and is currently under investigation.