Biology subjects

Saunders, S. E.

Publications and source records attributed to Saunders, S. E..

3 recordsLinked to original sources

bioRxiv2025

Autonomic reflex plasticity associates with time-dependent SUDEP susceptibility in a murine model with hyperactive stress circuits

Sudden unexpected death in Epilepsy (SUDEP) is the leading cause of death in patients with Epilepsy. Although SUDEP results from cardiorespiratory arrest, its underlying mechanisms are poorly understood. Considering the significant association between stress-related disorders and Epilepsy, we hypothesized that stress exaggerates autonomic reflexes critical in cardiorespiratory function and that these exaggerated reflexes increase susceptibility to SUDEP. Experiments were performed using a novel mouse model of SUDEP where hyperreactivity of central corticotropin-releasing hormone (CRH) neurons (Kcc2/Crh) predisposes mice to SUDEP in the weeks following seizure induction based on the ventral intrahippocampal kainate (vIHKA) model of chronic Epilepsy. In our study, the vIHKA model was employed in both wild-type (WT) and Kcc2/Crh mice while they were monitored with EEG and ECG using in vivo telemetry and underwent terminal autonomic reflex testing at time points when mortality peaked and plateaued. A resting tachycardia developed by one week following vIHKA injection but subsided by day 30 in both WT and Kcc2/Crh mice. During spontaneous seizures, Kcc2/Crh mice had more pronounced reflex-like ictal bradycardias compared to WT controls that notably occurred prior ([~]10 sec) to seizure termination. vIHKA injection promoted time-dependent exaggeration of autonomic reflexes, with Kcc2/Crh mice exhibiting robust autonomic disturbances compared to WT controls, including a pronounced serotonin-mediated Bezold Jarisch reflex. Taken together, our findings indicate that increased autonomic disturbance burden parallels time-dependent SUDEP susceptibility in mice with hyperreactive stress circuits.

neuroscience↗

bioRxiv2023

Compensatory changes in GABAergic inhibition are differentially expressed in the respiratory network to promote function following hibernation

BackgroundNeural circuits produce reliable activity patterns despite disturbances in the environment. For this to occur, neurons elicit synaptic plasticity during perturbations. However, recent work suggests that plasticity not only regulates circuit activity during disturbances, but these modifications may also linger to stabilize circuits during future perturbations. The implementation of such a regulation scheme for real-life environmental challenges of animals remains unclear. Amphibians provide insight into this problem in a rather extreme way, as circuits that generate breathing are inactive for several months during underwater hibernation and use compensatory plasticity to promote ventilation upon emergence. ResultsUsing ex vivo brainstem preparations and electrophysiology, we find that hibernation in American bullfrogs reduces GABAA receptor (GABAAR) inhibition in respiratory rhythm generating circuits and motor neurons, consistent with a compensatory response to chronic inactivity. Although GABAARs are normally critical for breathing, baseline network output at warm temperatures was not affected. However, when assessed across a range of temperatures, hibernators with reduced GABAAR signaling had greater activity at cooler temperatures, enhancing respiratory motor output under conditions that otherwise strongly depress breathing. ConclusionsHibernation reduces GABAAR signaling to promote robust respiratory output only at cooler temperatures. Although animals do not ventilate lungs during hibernation, we suggest this would be beneficial for stabilizing breathing when the animal passes through a large temperature range during emergence in the spring. More broadly, these results demonstrate that compensatory synaptic plasticity can increase the operating range of circuits in harsh environments, thereby promoting adaptive behavior in conditions that suppress activity.

physiology↗

bioRxiv2020

RAS-inhibiting biologics identify and probe druggable pockets including an SII-α3 allosteric site.

RAS mutations are the most common oncogenic drivers across human cancers, but there remains a paucity of clinically-validated pharmacological inhibitors of RAS, as druggable pockets have proven difficult to identify. We have identified two RAS-binding Affimer proteins, K3 and K6, that inhibit nucleotide exchange and downstream signalling pathways with distinct isoform and mutant profiles. Affimer K6 is the first biologic to bind in the SI/SII pocket, whilst Affimer K3 is the first non-covalent inhibitor of the SII region, revealing a novel RAS conformer with a large, druggable SII/3 pocket. This work demonstrates the potential of using biologics with small interface surfaces to select novel druggable conformations in conjunction with pharmacophore identification for hard-to-drug proteins.

molecular biology↗