title: Maladaptive Homeostatic Plasticity
title: Impact of Prolonged Silencing on Cellular Hyperexcitability
titleType: Subtitle
Creators: name: Wise, Derek Lindblad
Publisher: name: Brandeis University
Year: 2023
Subjects: Calcium Imaging
Cortex
Homeostasis
Organotypic
Slice Culture
Epilepsy

description: Homeostatic plasticity is a countervailing and necessary balance to a neural system capable of learning. When firing rates change over time, perhaps as a result of learning causing connections to vie for influences on a cell’s output, firing rate homeostasis is the force that bidirectionally enforces stability. Taken to its logical extreme, the tendency for cells that fire together to wire together (Hebbian plasticity) would mean that any reciprocally connected circuit would eventually fire perfectly synchronously and essentially all the time. That doesn’t happen in practice, and one reason is that cells have a set point for the amount of firing over a given period of time they should engage in, and they return to it by adjusting the strength of their input (synaptic scaling) and their input/output transformation (intrinsic excitability) among other potential parameters.The work packaged in this thesis fleshes out the issues of having such an overarching and powerful compensatory regulatory system control the firing rate of cells. The first included chapter, a work-in-progress collaboration with Dr. Vera Valakh and Dr. Yasmin Escobedo Lozoya, describes the efforts I’ve made to analyze superresolution images from the Zeiss Airyscan system. Fluorescently-tagged synapses are not trivial to identify or quantify, and the thousands in each image stack make it impractical to do by hand. We want to use well-validated and biologically-justified thresholding techniques to automate this analysis, and I employed our current system on a pilot experiment on slices that have been deprived of activity for several days to better understand the homeostatic response they’ve enacted.
description: Second, my work with Dr. Vera Valakh expands our understanding of one of the mechanisms that reins in homeostatic plasticity; when three particular genes repurposed from a circadian circuit are knocked out, animals have seizures that are very consistent with a homeostatic misregulation. It turns out that slice cultures with these genes missing are also especially reactive to activity silencing, leading us to conceptualize this gene family as a constraining arm of the homeostatic response.
description: Finally, I’ll present my incipient paper expanding prior work indicating that prolonged silencing can force developing circuits into lifelong hyperexcitability. I established a model system, in organotypic culture of mouse cortex, to explore this vulnerability mechanistically and I have identified some of the relevant forms of homeostatic plasticity at work.
description: Assessed as a single program of study, we learn from these inquiries that while homeostatic firing rate plasticity is a requirement for proper circuit function in neural systems, it is also a point of vulnerability for significant failure related to activity levels. Cells having a way to adjudicate their own activity levels so poignantly, after all, means that any time this system is misapplied it will have significant consequences.