Role of the Planar cell polarity signaling in shaping thorny excrescence specificity with functional circuit wiring during development and aging – THORNEX

Our goal is to decipher how PCP signaling modulates complex synaptic structures underlying our memory abilities. Since the initial description of famous patient HM’s amnesia, it has been indisputably established that functional integrity of the hippocampus is crucial for declarative memory, our capability to consciously recall the past, especially for its episodic component referring to the remembering of “what happened, where and when”. This fundamental capability diminishes during aging. In the hippocampus, the dentate gyrus-CA3 circuit is more affected than other regions during aging and is abnormally impaired in AD, resulting in diverse behavioral consequences, from loss of episodic memory to disorientation and dementia. Surprisingly, several genes and proteins associated with early neural development, particularly neuronal migration and axonal outgrowth, seem to play central roles in aging-related disorders. Amongst these are members of the Wnt/PCP signaling, a conserved signaling pathway known to shape tissues during development via the regulation of adhesion complexes and cytoskeleton dynamics that our lab has been studying for more than 15 years now. Work from our lab (Montcouquiol/Sans) reveals specific behavioral consequences to brain-specific disruptions of PCP signaling in mice (Moreau et al, J. Neurosci. 2010; Hilal et al, 2017; Ezan et al., submitted; or Robert et al., in press). Mechanistically, we still know little about Vangl2-dependent mechanisms during brain development and even less during aging. Preliminary data from our lab show that Vangl2 is enriched in the developing hippocampus and notably granule cells of the dentate gyrus and CA3 pyramidal neurons. We have recently showed that this early expression permits Vangl2 to control neuronal outgrowth of young hippocampal neurons [Dos Santos Carvalho et al., 2020], most probably through the modulation of adhesion molecules. Importantly, many adhesion molecules are needed for the MfB/TE synapse in the CA3 region of the hippocampus where we also observed an enrichment of Vangl2 at stages that coincides with the increasing morphological complexity and maturation of the MfB/TE giant synapse. We also show that the loss of Vangl2 during development can result in selective mild cognitive deficits early in life but can unexpectedly improve memory in aging animals. These results have strong relevance in the field of cognitive aging, as many data have suggested that a key neural substrate for aging-related memory decline is a shift in hippocampal network dynamics.
In this project, we hypothesize that Vangl2-dependent signaling participates in the structural formation and shaping of "thorny excrescence" synapse in the hippocampus, and that a loss of Vangl2 will disrupt the organization of the structure and affects specific cognitive processes necessary throughout life. To address this, we propose to characterize the role of Vangl2 on the structurally complex MfB/TE giant synapse, and study how its deletion affects specific brain function during development and in aging. For this, we will combine biochemistry and molecular and cellular biology approaches, 3D imaging and specific behavioral tasks sensitive to aging, so called “hippocampal-dependent” tasks that have been designed to capture elementary properties and components of declarative memory in animals. This project will provide novel conceptual insights into mechanisms required to build functional synapses and to maintain them during aging.