Physiology seminars

The Ca2+ modulated pulsatile secretions of glucagon and insulin by pancreatic α and β cells play a key role in glucose metabolism and homeostasis. However, how different types of cells in the islet couple and coordinate to give rise to various Ca2+ oscillation patterns and how these patterns are being tuned by paracrine regulation are still elusive. Here we developed a microfluidic device to facilitate long-term recording of islet Ca2+ activity at single cell level and found that islets show heterogeneous but intrinsic oscillation patterns. The α and β cells in an islet oscillate in antiphase and are globally phase locked to display a variety of oscillation modes. A mathematical model of islet oscillation maps out the dependence of the oscillation modes on the paracrine interactions between α and β cells. Our study reveals the origin of the islet oscillation patterns and highlights the role of paracrine regulation in tuning them.

Synaptic scaling is a homeostatic normalization mechanism that preserves relative synaptic strengths by adjusting them with a common factor. This multiplicative change is believed to be critical, since synaptic strengths are involved in learning and memory retention. Further, this homeostatic process is thought to be crucial for neuronal stability, playing a stabilizing role in otherwise runaway Hebbian plasticity [1-3]. Synaptic scaling requires a mechanism to sense total neuron activity and globally adjust synapses to achieve some activity set-point [4]. This process is relatively slow, which places limits on its ability to stabilize network activity [5]. Here we show that this slow response is inevitable in realistic neuronal morphologies. Furthermore, we reveal that global scaling can in fact be a source of instability unless responsiveness or scaling accuracy are sacrificed." "A neuron with tens of thousands of synapses must regulate its own excitability to compensate for changes in input. The time requirement for global feedback can introduce critical phase lags in a neuron’s response to perturbation. The severity of phase lag increases with neuron size. Further, a more expansive morphology worsens cell responsiveness and scaling accuracy, especially in distal regions of the neuron. Local pools of reserve receptors improve efficiency, potentiation, and scaling, but this comes at a cost. Trafficking large quantities of receptors requires time, exacerbating the phase lag and instability. Local homeostatic feedback mitigates instability, but this too comes at the cost of reducing scaling accuracy." "Realization of the phase lag instability requires a unified model of synaptic scaling, regulation, and transport. We present such a model with global and local feedback in realistic neuron morphologies (Fig. 1). This combined model shows that neurons face a tradeoff between stability, accuracy, and efficiency. Global feedback is required for synaptic scaling but favors either system stability or efficiency. Large receptor pools improve scaling accuracy in large morphologies but worsen both stability and efficiency. Local feedback improves the stability-efficiency tradeoff at the cost of scaling accuracy. This project introduces unexplored constraints on neuron size, morphology, and synaptic scaling that are weakened by an interplay between global and local feedback.

Recent developments in induced pluripotent stem cell (iPSC) technology have enabled easier access to human cells in vitro. With increasing availability of human iPSC-derived neurons, both healthy and disease cell lines, screening compounds for neurodegenerative diseases on human cells can potentially be performed in the earlier stages of drug discovery. To accelerate the functional characterization of iPSC-derived neurons and the effect of compounds, reproducible and relevant results are necessary. In this webinar, the speakers will: Introduce high-resolution functional imaging of human iPSC-derived neurons Showcase how to extract functional features of hundreds of cells in a cell culture sample label-free Discuss electrophysiological parameters for characterizing the differences among several human neuronal cell lines