Biology subjects

Farrell, J. S.

Publications and source records attributed to Farrell, J. S..

7 recordsLinked to original sources

bioRxiv2026

Connexin 40 deficiency alters the temporal profile of postictal oxygen dynamics following focal seizures.

Epilepsy is increasingly recognized as a disorder involving both neuronal and vascular dysfunction. While connexin signaling has been implicated in epileptogenesis, the contribution of vascular connexins to seizure associated cerebrovascular pathology remains poorly understood. Connexin40 (Cx40) is an endothelial gap junction protein that plays a crucial role in vascular communication and blood-flow regulation. Seizures induce dynamic changes in cerebral perfusion and oxygenation, including prolonged postictal hypoperfusion/hypoxia. To determine whether Cx40 influences postictal hypoxia following focal seizures, we examined seizure characteristics and postictal oxygen dynamics in Cx40 knockout (Cx40-/-) mice using an established focal hippocampal seizure model. Electrically kindled seizures were elicited in wild-type and Cx40-/- mice, and local hippocampal tissue oxygenation was continuously monitored before and after seizure induction. Seizure duration did not differ between genotypes, indicating comparable seizure severity. Interestingly, Cx40 deletion altered the temporal pattern of postictal oxygen recovery, producing greater early hypoxia and a delayed secondary rebound in pO2 despite similar peak oxygen levels and overall hypoxic burden. These findings demonstrate that loss of Cx40 selectively alters the temporal profile of postictal oxygen dynamics without affecting seizure duration. Taken together, the results suggest that endothelial gap junctional communication contributes to postictal vascular recovery and identify Cx40 as a potential modulator of seizure associated neurovascular dysfunction.

neuroscience↗

bioRxiv2026

Hippocampal microcircuits constrain the generation of epileptiform activity

Epilepsy is largely characterized using macroscale measures of neural activity, such as electroencephalography, which are unable to resolve the underlying cellular-level substrates of pathological activity. Although there is a growing understanding that hippocampal microcircuits, comprised of distinct CA1 principal cells (PCs), inhibitory neurons, and input/output relationships, route information through parallel hippocampal pathways, the relevance of this microscale organization in epilepsy is poorly understood. To address this gap, we focally knocked out the {beta}3 subunit of the GABAA receptor from CA1 PCs, which strongly impaired parvalbumin-mediated inhibition to deep PCs, but not superficial PCs - potentially promoting a microcircuit-selective epilepsy manifestation. Indeed, we observed robust interictal epileptiform discharges (IEDs) at the site of focal knockout with features consistent with a potential CA2-to-deep CA1 PC generation mechanism. In line with prior observations that CA2 inputs potently drive deep PCs under physiological conditions, IEDs could be reliably evoked by optogenetic stimulation of CA2 in {beta}3 focal knockout mice. Resolving cellular activity across the CA1 PC network during IEDs, in vivo 2-photon calcium imaging demonstrated stronger activation of deep versus superficial PCs. Altogether, these data demonstrate that macroscopic electrophysiological patterns such as IEDs can have underlying microcircuit constraints, which has important implications for designing therapies that target the underlying microcircuit generators of epileptiform activity.

neuroscience↗

bioRxiv2026

FMR1 reduction alters cellular and circuit properties in human cortex

Transcriptional silencing of FMR1 results in Fragile X syndrome (FXS), the leading inherited cause of intellectual disability (ID) and autism. The Fmr1-/y mouse model has been used to identify FXS disease mechanisms, whereas mechanistic insights from human brain are lacking. By leveraging organotypic human cortical slices and viral tools to reduce FMR1 expression, we create a new model that captures cell type-specific transcriptomic changes similar to FXS patient cortex that are not seen in the Fmr1-/y mouse. Among these are ion channel subunit changes in deep layer pyramidal neurons, which are consistent with a robust hyperexcitability seen by whole-cell patch-clamp recordings, and increased synchronized activity revealed by 2-photon calcium imaging. Together, this work defines the impact of FMR1 reduction in human cortex and provides a new model for testing therapeutic interventions in FXS.

neuroscience↗

bioRxiv2025

Toothy: an interactive platform for dentate spike curation

Dentate spikes (DSs) are hippocampal population events that occur during low-arousal states, defined by large-amplitude positive voltage peaks recorded in the hilus of the dentate gyrus (DG). DSs can be classified into two types (DS1 and DS2), with DS2 linked to transient increases in arousal, brain-wide neural activation, and functional relevance for memory encoding. Despite growing interest in their physiological and functional properties, no standardized framework exists for detecting and classifying DSs. We present Toothy, an open-source tool for DS detection and classification in large-scale electrophysiological recordings. Toothy offers a modular and interactive workflow comprising three key steps: (1) ingestion and preprocessing of local field potential (LFP) recordings, (2) detection of hippocampal population events, and (3) classification of DS types using peri-event current source density (CSD) profiles. To support both flexibility and reproducibility, features include compatibility with multiple recording formats, customizable processing parameters, interactive event review tools, and comprehensive logging of event detection and classification parameters. In addition to DS detection, Toothy can also detect sharp wave-ripples (SPW-Rs; an oscillatory population event recorded in the CA1 region), enabling comparative analysis between DSs and SPW-Rs. Toothy provides a standardized, reproducible pipeline for DS detection and classification, advancing broader efforts towards investigating hippocampal dynamics across diverse settings.

neuroscience↗

bioRxiv2022

Sudden unexpected death in epilepsy is prevented by blocking postictal hypoxia

Epilepsy is at times a fatal disease. Sudden unexpected death in epilepsy (SUDEP) is the leading cause of mortality in people with intractable epilepsy and is defined by exclusion; non-accidental, non-toxicologic, and non-anatomic causes of death. While SUDEP often follows a bilateral tonic-clonic seizure, the mechanisms that ultimately lead to terminal apnea and then asystole remain elusive and there is a lack preventative treatments. Based on the observation that discrete seizures lead to local vasoconstriction, resulting in hypoperfusion, hypoxia and behavioural disturbances in the forebrain (Farrell et al., 2016), we reasoned that similar mechanisms may play a role in SUDEP when seizures invade the brainstem. Here we tested this neurovascular-based hypothesis of SUDEP in awake non-anesthetized mice by pharmacologically preventing seizure-induced vasoconstriction, with cyclooxygenase-2 or L-type calcium channel antagonists. In both acute and chronic mouse models of SUDEP, ibuprofen and nicardipine extended life. We also examined the potential role of spreading depolarization in the acute model of SUDEP. These data provide a proof of principle for the neurovascular hypothesis of SUDEP and the use of currently available treatments to prevent it.

neuroscience↗

bioRxiv2020

A fluorescent sensor for spatiotemporally resolved endocannabinoid dynamics in vitro and in vivo

Endocannabinoids (eCBs) are retrograde neuromodulators that play an important role in a wide range of physiological processes; however, the release and in vivo dynamics of eCBs remain largely unknown, due in part to a lack of suitable probes capable of detecting eCBs with sufficient spatiotemporal resolution. Here, we developed a new eCB sensor called GRABeCB2.0. This genetically encoded sensor consists of the human CB1 cannabinoid receptor fused to circular-permutated EGFP, providing cell membrane trafficking, second-resolution kinetics, high specificity for eCBs, and a robust fluorescence response at physiological eCB concentrations. Using the GRABeCB2.0 sensor, we monitored evoked changes in eCB dynamics in both cultured neurons and acute brain slices. Interestingly, in cultured neurons we also observed spontaneous compartmental eCB transients that spanned a distance of approximately 11 m, suggesting constrained, localized eCB signaling. Moreover, by expressing GRABeCB2.0 in the mouse brain, we readily observed foot shock-elicited and running-triggered eCB transients in the basolateral amygdala and hippocampus, respectively. Lastly, we used GRABeCB2.0 in a mouse seizure model and observed a spreading wave of eCB release that followed a Ca2+ wave through the hippocampus. Thus, GRABeCB2.0 is a robust new probe for measuring the dynamics of eCB release under both physiological and pathological conditions.

neuroscience↗

bioRxiv2020

The Neurovascular Basis of Postictal Amnesia

Long-lasting confusion and memory difficulties during the postictal state remain a major unmet problem in epilepsy that lacks pathophysiological explanation and treatment. We previously identified that long-lasting periods of severe postictal hypoperfusion/hypoxia, not seizures per se, are associated with memory impairment after temporal lobe seizures. While this observation suggests a key pathophysiological role for insufficient energy delivery, it is unclear how the networks that underlie episodic memory respond to vascular constraints that ultimately give rise to amnesia. Here, we focused on cellular/network level analyses in the CA1 of hippocampus in vivo to determine if neural activity, network oscillations, synaptic transmission, and/or synaptic plasticity are impaired following kindled seizures. Importantly, the induction of severe postictal hypoperfusion/hypoxia was prevented in animals treated by a COX-2 inhibitor, which experimentally separated seizures from their vascular consequences. We observed complete activation of CA1 pyramidal neurons during brief seizures, followed by a short period of reduced activity and flattening of the local field potential that resolved within minutes. During the postictal state, constituting tens of minutes to hours, we observed no changes in neural activity, network oscillations, and synaptic transmission. However, long-term potentiation of the temporoammonic pathway to CA1 was impaired in the postictal period, but only when severe local hypoxia occurred. Lastly, we tested the ability of rats to perform object-context discrimination, which has been proposed to require temporoammonic input to differentiate between sensory experience and the stored representation of the expected object-context pairing. Deficits in this task following seizures were reversed by COX-2 inhibition, which prevented severe postictal hypoxia. These results support a key role for hypoperfusion/hypoxia in postictal memory impairments and identify that many aspects of hippocampal network function are resilient during severe hypoxia except for long-term synaptic plasticity.

neuroscience↗