Form function relation implications of synaptic design on neuronal function

Abstract

In the world around us, form and function are closely linked together. Each continually directing the other. Our brain is no exception. Its neural circuitry dictates behavior and our daily experiences, in turn, rewire the brain. In the same spirit, I have explored the intricate relation between the form and function of hippocampal synapses in my thesis. The hippocampus, a deep structure in the limbic system, plays an essential role in storing and recollecting episodic memories. I have chosen to study two distinctly different synapses from the trisynaptic loop in this brain structure: the Schaffer collaterals and the mossy fibers to enable a comparative understanding of the inner workings of the systems. One of the most important properties of these synapses, which enables memory formation, is plasticity the ability to modulate their synaptic strength in an activity-dependent manner. I have focussed on investigating the mechanistic cause behind a specific kind of plasticity called short-term plasticity (STP). Schaffer collaterals originate in the CA3 and project onto CA1 creating a small synapse containing a single active zone, with barely ten vesicles in the readily releasable pool (RRP). The endoplasmic reticulum (ER) is extensively present in the axons. Mossy fibers, on the other hand, are large, hosting tens of active zones that incorporate hundreds of vesicles in their RRP. Rapid short-term plasticity manifests in both these synapses, but very differently, owing to their distinct form. Short bursts of stimuli increase synaptic efficacy in both cases although mossy fibers sustain the elevated synaptic strength for much longer. Sustained stimulus, on the other hand, depresses Schaffer collaterals while it strengthens mossy fibers. Despite decades of research into these synapses, our understanding of their form-function is still murky. I have employed a computational approach to shed light on their underlying mechanisms. We developed physiologically realistic spatial models of the CA3 pyramidal neuron and the