Characterizing the Contribution of Pannexin-1 to Seizure Susceptibility in Mice
Bibliographic record
Abstract
Epilepsy affects nearly 50 million people. Approximately one third of that population is resistant to modern treatment options. Despite decades of research, our understanding of epileptogenesis – the process by which a brain transitions from healthy activity to pathologic – remains unclear. A ubiquitously expressed, ATP-permeable, large-pore forming protein, Pannexin-1 (Panx1), has recently emerged as a contributor to neuronal hyperexcitability. Within this dissertation, I propose that Panx1 acts as a key contributor to the dynamics observed during epileptic activity. I set out to prove this largely through the electrophysiological characterization of a Panx1 genetic knockout mouse model. The electrophysiological insights are supported through additional behavioral and molecular experiments. Characterization of single-cell patch clamping reveals that cortical pyramidal neurons of Panx1 knockouts demonstrate a hyperpolarized resting membrane potential. This suggests Panx1 deficiency contributes towards a hypoexcitable phenotype. Pursuing this line of inquiry, I set out to test three distinct models of epilepsy and seizure: 1) acute electrical kindling, 2) acute injection of pentylenetetrazol in vivo, and 3) 4-aminopyridine incubated with in vitro brain slices. In each of these models, Panx1 knockouts demonstrate seizure-resistance. In this dissertation, I also explore the potential mechanisms behind Panx1-dependent excitability. In doing so, I find that purinergic receptors P2X7 and P2Y1, sensitive to extracellular ATP released by Panx1, are differentially regulated in Panx1 knockout mice. When antagonized in wild-type mice, these receptors recapitulate the Panx1 knockout phenotypic seizure resistance. Conversely, when the receptors are stimulated with ATP in Panx1 knockout mice, the animal demonstrates a return to normal susceptibility to a convulsant stimulus. In sum, this work reveals that Panx1, through the action of its permeant ATP acting on P2 receptors, is a contributor to setting an epileptic state. This highlights new avenues for therapeutic targeting of Panx1 for the development of anti-epileptic drugs.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".