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 mossy fiber bouton to explore the role of synaptic form in orchestrating calcium signaling and plasticity. Such in-silico methods provide us with the ability to probe complex interactions between multiple components in small spaces that are difficult to study otherwise. Our model predicts that presynaptic ER is critical in generating the observed STP in CA3-CA1 synapses. SERCA pumps maintain low release probability and contribute to residual calcium. Blocking ER disrupts facilitation as seen in animal models of Alzheimer’s, underscoring the importance of ER in normal function. At the mossy fiber synapse, the crosstalk between active zones, local buffer saturation, and the calcium sensor synaptotagmin-7 make distinct contributions to STP. With subsequent stimuli, the local capacity to buffer calcium decreases and the residual calcium increases, so does the spatial extent of the calcium signal, which ultimately increases the overlap with nearby active zones. This cross-talk further elevates residual calcium levels, augmenting vesicle release. In addition, synaptotagmin-7 shows progressive increase in bound calcium with each subsequent calcium influx, leading to increased asynchronous release. The combined effect of these phenomena results in a sharp increase in neurotransmitter release that is capable of triggering an action potential in the postsynaptic neuron. Moreover, we find that STP is essential in decorrelating input signals in MF, thereby confirming its role in temporal pattern separation.