Molecular Mechanisms underlying the structural plasticity of dendritic spines

Although dendritic spine formation and elimination are strongly correlated to memory formation, their causal relationship remain to be determined. The main obstacle in assessing causality between dendritic spine plasticity and memory correspond to our lack of knowledge regarding their molecular mechanisms. An understanding of the molecular events leading to spine formation/elimination will allow us to identify molecular marker for newly formed spines or spines tagged for elimination. By manipulating these markers, we hope to be able to selectively interfere with these structural plasticity events and thus be able to evaluate their causal role in memory. To this end, we will first attempt to elucidate the molecular basis of spine formation /elimination using in vitro models to subsequently manipulate these processes in vivo in a behaving animal and thus assess their causative role in memory formation. We will meet these goals using a combination of in vitro/in vivo genetic manipulations and 2-photon imaging microscopy.

Alzheimer disease targets dendritic spines

Given that dendritic spines seem to correspond to the most basic unit of memory storage, it is possible that Alzheimer’s disease (AD) might trigger memory dysfunction by targeting dendritic spines. As of today, numerous studies have shown that Alzheimer disease is strongly associated with a decrease in the number of dendritic spines in both transgenic animal model of AD and human AD patients. More importantly, dendritic spine loss is strongly correlated with the cognitive deficits associated to AD suggesting a causal relationship. It is less clear, however, what aspect of dendritic spine plasticity is affected during the progression of the disease as both a decrease in dendritic spine formation or increase in dendritic spine elimination might lead to the overall loss in dendritic spines. Again, progress in this area have been hindered by the lack of knowledge regarding the molecular mechanisms underlying dendritic spine plasticity. In this project, we will take advantage of the insights gained in the previous section to elucidate the particular molecules and events leading to the net loss of dendritic spines. The ultimate goal is to correct these alterations in dendritic spine plasticity as a way to prevent or halt the progression of Alzheimer’s disease.