UC San Diego

The ability to adapt is a hallmark of the brain. Unlike most cells in the body, most neurons are not replaced as one ages.Therefore, neurons are highly plastic, modifying themselves biochemically and structurally across multiple lengthscales in a process called synaptic plasticity. The backbone of these modifications lies in a neuron's ability to modulate the strength of its synapses, the connections between neurons. Most excitatory synapses are housed in small subcompartments, ~ 0.1 femtoliter in volume, called dendritic spines. Dendritic spines have characteristic shapes and sizes that correlate to disease, learning, and aging. These spine shapes and sizes change during synaptic plasticity and more specifically structural plasticity. When a dendritic spine receives a signal, it triggers complex biochemical signaling networks that can modulate the synaptic strength of the dendritic spine, or its synapse, by modulating the number of receptors on its membrane, amongst other modifications. Therefore, there is a coupling and feedback between the biochemical signaling underlying synaptic plasticity and the morphology of dendritic spines.

In this work, we utilize computational and mathematical models to investigate this structure-function relationship in dendritic spines, as well as in larger lengthscale components such as dendrites and neurons. We start with an example of extreme structural plasticity, where a biochemical signal can rupture connections between cells. We show that biochemical signaling can trigger mechanical forces to modulate cellular morphology and neural connections. Next, we investigate how neuronal morphology influences biochemical signaling more closely in the context of synaptic plasticity in dendritic spines. We consider different timescales of signaling starting with voltage propagation during spine activation, and calcium influx into dendritic spines of different morphologies. We find that spine morphology and ultrastructure can impact signaling dynamics even at these early timescales. Finally, we use both a compartmental model and a spatial model to consider the biochemistry underlying synaptic plasticity, and how signaling and receptor trafficking couple during synaptic plasticity. We find that model architecture filters the influence of upstream signaling on synaptic plasticity readouts and that spine morphology, in particular spine size, can act to regulate synaptic plasticity to prevent excessive receptor change. This work strives to emphasize the coupling between spine morphology and biochemical signaling networks that govern synaptic plasticity, creating a foundation for future work to investigate structural plasticity in more detail.