Microtubule and actin coordination by structural MAPs – MAMAs

In mature neurons, the cytoskeleton plays a crucial role in the formation and activity of synapses, which constitute communication sites between neurons and are composed of pre-synaptic (axon terminals) and post-synaptic (dendritic spines) compartments. Cognitive functions, such as learning and memory, rely at least partly on synaptic plasticity, i.e. the ability of synapses to change their strength over time. Synaptic plasticity events are characterized by modifications of dendritic spines including variations in their morphology, intracellular trafficking and cytoskeleton arrangement. For many years, actin was thought to be the main cytoskeletal element controlling spine morphology, but more recent studies have revealed that microtubules transiently penetrate in spines where they influence actin organisation and modulate spine shape and functions. Thus, a tight coordination of microtubule and actin dynamics is required for the proper functionality of synapses. To date, only a few effectors have been identified as linkers between microtubules and actin in spines, mainly including complexes of microtubule- and actin-binding proteins. In that context, structural MAPs (Microtubule-Associated Proteins) defined as proteins interacting all along the microtubule wall represent exciting candidates, since they appear to also interact with actin. Such a duality could allow a direct coupling of microtubules and actin in spines, driving the coordination of dynamics and organisation of the two cytoskeletons. How these effectors control the microtubule/actin crosstalk during synaptic plasticity is far from being elucidated. Such a question represents an emerging and exciting research issue in both the cytoskeleton and neuroscience fields.
The aim of the MAMAs program is to elucidate molecular mechanisms of the microtubule/actin crosstalk during synaptic plasticity. To tackle this issue, we will make use of our expertise in two structural and neuronal MAPs for which we have described actin-binding properties in vitro, namely tau and MAP6. Tau and MAP6 are localized in spines where they are crucial for synaptic plasticity. Indeed, tau- and MAP6-deficient animals, which are used as models for studying cognitive defects related to Alzheimer’s disease and schizophrenia respectively, exhibit severe impaired synaptic functions. These MAPs are thus very good candidates to decipher the cytoskeleton remodelling that underlies synaptic plasticity and thereby cognition. We will determine the molecular basis of tau and MAP6 interaction with microtubules, actin and both cytoskeletons in reconstituted cell-free systems. Our second aim is to understand how these properties are utilized to regulate microtubule and actin behaviour in dendritic spines of mature neurons, which represent the most pertinent cell model to analyse synaptic plasticity. Finally, our last and most challenging goal is to establish for the first time a 3D map of microtubule and actin co-organisation in spines by cryo-electron tomography, a unique tool allowing the preservation of native cytoskeleton architecture in cells at the nanometre scale.
To perform this project, we built a consortium of three partners with complementary expertise and skills covering in vitro reconstitution of cytoskeleton properties (Arnal & Andrieux teams), structural analysis by cryo-electron microscopy techniques (Schoehn & Arnal teams) and cellular biology in primary lived neurons (Andrieux & Arnal teams).
Overall, if granted, this program should provide new insights in the molecular pathways involved in neuronal maintenance and activity and help to identify molecular dysfunctions leading to neuronal pathologies associated with cytoskeletal abnormalities.