Project Summary The goal of this Phase II proposal is to develop a commercial “plug and play”, user-friendly, powerful and reliable dynamic clamp system specifically designed for neuronal applications. Our product will enable all neuronal electrophysiologists to be able to perform sophisticated dynamic clamp experiments, without any requirement for programming, engineering, or mathematical modeling skills. Our product is an integrated package of hardware and software specifically for neuroscience applications, focusing on the specific stability and reliability needed for routine neuronal electrophysiology and the large array of ion channels found in the nervous system. In Phase I, we developed the critical combination of software, operating system, and hardware to achieve high speeds, and, most importantly, the high reliability needed for this product. The hardware and software innovations that make this system reliable and stable include a digitally modulated conductance clamp mode. This new innovation greatly expands the stability of the system during the rapid voltage changes that occur during neuronal action potentials. Our advances are made possible by proprietary software containing trade secrets, novel patented and patent pending instrumentation and the unique skill set of our team. Our system is also the first dynamic clamp system capable of using Ca2+ (and other fluorometric signals) to interact with current amplitudes and gating behavior. In Phase I, we found that the main limitation to introducing optical signals into dynamic clamp was bandwidth. In Phase II, we have a matched a patent-pending custom low-latency photodetector system that we developed explicitly for use in dynamic clamp. The three aims of this project are: 1) Develop Graphically Oriented Validated Model Channel Libraries. This aim is strongly customer driven, based on feedback from our I-Corps interviews. The biggest barrier to using dynamic clamp in the laboratory is difficulty implementing models. We will make dynamic clamp as easy to use as an app on your phone. 2) Develop and validate an advanced version of the Cybersolver for intuitive model building. We will build an intuitive interface that matches how electrophysiologists actually analyze their data. Machine intelligence will help guide users through the process and avoid common errors. They will be able to produce custom models that run, without problem, on the Cybercyte. 3) Develop & Optimize Hardware for Customer-driven Features. This includes the need for more than just membrane voltage as an input. We will incorporate optical input signals. We will also include frequently requested features to improve the ease of use, speed of response, and an alternate “synthetic cell” mode of operation. Completion of these aims will result in an advanced commercial neuronal dynamic clamp system, which is powerful, reliable, but plug and play to install, and simple to use.

This project will build a specialized system that allows computers to become integral parts of neurons. By interacting with a neuron as it responds to stimuli, we can better understand how and why some mutations cause seizures and other mental and neurological disorders. We can also use it to develop better medicines to treat these disorders.