Neuronal Synaptic Plasticity And Biochemical Signaling Affected By Dendritic Spine Morphology: A Modeling Study

Fragile X syndrome (FXS) is caused by mutations in the FMR1 gene. FXS is the most frequently inherited disease related to mental retardation and its mutations are highly associated with Autism. Perhaps the most characteristic cellular phenotype of FXS is abnormal dendritic spine morphology; dendritic spines are the site of most excitatory synapses in the brain. Spine abnormalities have been associated with memory, learning, motor-sensory, and behavior disorders. Our purpose is to understand how changes in spine morphology associated with FXS affect biochemical signaling related to synaptic plasticity, a cellular mechanism of learning and memory. For this purpose we will build a data base of the size and shapes of dendritic spines affected by FXS from the literature. Using these structural models we will simulate the diffusion and reaction of multiple molecules involved in synaptic plasticity to determine how spine shape affects biochemical information processing. We expect to see a change in the effectiveness of activation of the reactions involved in synaptic plasticity in spines showing strong structural abnormalities due to FXS when compared to healthy spines. Our work will provide quantitative results to link FXS mutations that cause dendritic structural abnormalities to the effectiveness of expressing synaptic activity, thus providing testable predictions.