Biology subjects

Parrish, R. R.

Publications and source records attributed to Parrish, R. R..

16 recordsLinked to original sources

bioRxiv2026

β-Hydroxybutyrate maintains energetically demanding neural functions during glucose deprivation

Ketone bodies are a major source of cerebral energy during fasting and the ketogenic diet, but whether they can independently sustain brain tissue metabolism when glucose is absent remains uncertain. This question is difficult to resolve in vivo because circulating glucose is maintained, even during starvation, through endogenous production. We therefore used an ex vivo brain preparation to examine the metabolic capacity of tissue supplied with {beta}-hydroxybutyrate (BHB) as the only exogenous fuel, isolating brain tissue from the primary endogenous glucose sources. Mitochondrial function was monitored following prolonged exposure to glucose-free, BHB-rich artificial cerebrospinal fluid, and tissue resilience was tested by inducing spreading depolarization, a severe energetic challenge that requires rapid restoration of ionic and metabolic homeostasis. Following acute reliance on BHB, mitochondria appeared to dynamically regulate electron transfer system function, utilizing lower O2 flux, while maintaining sufficient energetic reserves to preserve tissue ability to generate and recover from repeated spreading depolarizations. These findings demonstrate that BHB can independently maintain essential metabolic and functional properties of brain tissue in the absence of exogenous glucose. The results broaden our understanding of cerebral fuel flexibility and provide additional support for the use of ketogenic strategies in neurological disorders where tissue excitability, energy metabolism, or glucose availability may be altered. O_FIG O_LINKSMALLFIG WIDTH=182 HEIGHT=200 SRC="FIGDIR/small/730699v2_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@82e0a1org.highwire.dtl.DTLVardef@698703org.highwire.dtl.DTLVardef@1ee27aorg.highwire.dtl.DTLVardef@1a6d45e_HPS_FORMAT_FIGEXP M_FIG C_FIG Cerebral fuel flexibility: glucose and ketones{beta}-Hydroxybutyrate (BHB) supports continual mitochondrial oxygen flux, along with induction of and recovery from repeated spreading depolarizations in mouse brain tissue in the absence of glucose. These findings demonstrate that ketone-supported metabolism can sustain energetically demanding neural function through a distinct bioenergetic strategy. Created in BioRender. Parrish, R. (2026) https://BioRender.com/k92j91u.

neuroscience↗

bioRxiv2026

Seize the Data: A User-Friendly GUI for High-Resolution Analysis of Seizure Dynamics in HD-MEA Recordings

High-density multi-electrode arrays (HD-MEAs) generate large, complex datasets that are challenging to efficiently manage and analyze with existing tools, especially in open-source environments. To address this, we developed the BYU Seizure and Analytics Tool (YSA), an open-source graphical user interface (GUI) built in Python and C++ for efficient analysis and visualization of HD-MEA recordings. The YSA features raster plots, automated discharge detection and tracking, downsampling, playback, and export functions, enabling streamlined workflows for large-scale neural data. We demonstrate the utility of the tool in the context of seizure and status epilepticus (SE)-like activity, highlighting how the YSA facilitates rapid exploration of the spatiotemporal dynamics in brain networks. This platform provides an accessible and practical solution for HD-MEA data analysis, supporting a range of neuroscience applications. Significance StatementHigh-density multi-electrode arrays (MEAs) generate rich spatiotemporal datasets ideal for studying complex brain dynamics such as seizure activity. However, the size and complexity of these data often pose challenges for efficient analysis and interpretation. We present the BYU Seizure and Analytics Tool (YSA), an open-source graphical interface for intuitive visualization and exploration of MEA data. YSA enables users to navigate activity across the entire brain slice, identify relevant patterns, and easily export subsets for targeted analyses such as individual discharges. By making high-density seizure data more accessible and actionable, YSA streamlines analysis workflows and supports deeper insights into the spatiotemporal dynamics underlying seizure initiation and propagation in models of status epilepticus, pharmacoresistant epilepsy, and broader neural activity.

neuroscience↗

bioRxiv2025

Pharmacological inhibition of all known major inward cationic currents does not block the induction of spreading depolarizations

Spreading depolarization (SD) is a wave of profound cellular depolarization that propagates across central nervous system tissue and causes a near-complete collapse of ionic gradients. Implicated in neuropathologies including seizures, migraine with aura, traumatic brain injury, and stroke, SD is experimentally induced in animals by electrical stimulation, mechanical injury, hypoxia, elevated extracellular potassium, and various other techniques. Despite extensive research, the mechanisms underlying SD initiation remain unclear. Prior research in rodents found that simultaneously blocking sodium, calcium, and glutamatergic (AMPA and NMDA) channels prevents SD induction whereas inhibiting any two of these three currents is insufficient. This suggests that SD induction could be a product of overstimulation of any single known inward cationic current. However, some researchers propose that SD induction occurs via an unknown "SD channel." To further explore the role of known inward cationic currents in SD induction, we applied high potassium to two biological models, namely zebrafish and mice. First, we developed a novel ex vivo zebrafish model to assess SD induction in the optic tectum. Using KCl microinjection and DC local field potential recordings, we found that inhibition of sodium, calcium, and glutamatergic channels significantly decreased SD amplitude but never blocked SD induction in the zebrafish optic tectum. Similar pharmacological experiments in hippocampal mouse slices (CA1 subregion) also confirmed that SDs persist despite the same pharmacological cocktail. These findings suggest that additional mechanisms beyond sodium, calcium, and glutamatergic signaling contribute to SD induction, supporting the hypothesis that a currently unknown channel is critical in SD physiology.

neuroscience↗

bioRxiv2025

Human and Rodent Seizures Demonstrate a Dynamic Interplay with Spreading Depolarizations

Seizure termination has been linked to spreading depolarizations (SDs) in experimental epilepsy models, and SDs have recently been suggested to protect against seizures. The precise mechanism, however, remains unclear. Additionally, the co-occurrence of SDs with human seizures remains debated. In this study, we found that SDs are a prominent feature following ictal events in both human clinical recordings (n=20 seizures from 7 epilepsy patients) using direct-current amplifiers and in the 0 Mg2+ model of ictogenesis from rodent brain slices (n=17). Approximately one-third of rodent seizure-like events (SLEs) were associated with SDs, while all human seizures analyzed had associated infraslow shifts, a hallmark of SDs. SDs were more prominent in the lateral frontal, medial frontal, and lateral temporal lobes, as well as the insular cortex in human patients, but were observed in all recorded brain regions. In rodents, SDs clustered toward the end of ictal events, resulting in significantly shorter SLEs (SLE without SD: 32.60 {+/-} 5.31 s; SLE with SD: 16.03 {+/-} 4.45 s) and delayed onset of subsequent SLEs. These SDs also caused significant AC band silencing compared to SLEs without SDs. Interestingly, SLEs with SDs displayed significantly more low gamma activity during ictal events. Using ion- selective microelectrodes, we found no significant correlation between extracellular [K+] levels and SLEs ending in SDs, questioning the role of [K+]o in SD induction during seizures. We observed more heterogeneity in human seizures than in rodent SLEs, with some human seizures showing SD-associated termination and others demonstrating SDs in the middle of ictal events; such intra-seizure SDs were never observed in our rodent model. The human data, collected from patients with intractable epilepsy, demonstrate clear SD propagation during seizures and show that SDs appear and propagate, in multiple brain regions simultaneously with ictal events. Collectively, these results indicate that SDs are a hallmark of ictal activity and may contribute to seizure termination in both experimental and clinical settings. Furthermore, these findings provide unique insight into the neuronal dynamics that promote SD induction by showing that increased low gamma activity during SLEs is more predictive of SD induction than extracellular [K+] levels. We also add further support for the hypothesis that SDs are both anti- seizure and anti-ictogenic as they not only limit and delay subsequent ictal activity but also reduce the duration of SLEs. Taken together, these findings provide rationale for further exploration of SDs as a means to prematurely terminate life-threatening seizures.

neuroscience↗

bioRxiv2023

Variant Mapping Application: Customize And Annotate Figures Of Voltage-Gated Sodium Channel

Voltage-gated sodium ion channels allow for the initiation and transmission of action potentials. There is a high interest in research and drug development to selectively target these ion channels to treat epilepsy and other disorders such as pain. Scientific literature and presentations often incorporate maps of these integral membrane proteins with markers indicating gene mutations to highlight genotype/phenotype correlations. There is a need for automated tools to create high quality figures with mutation (variant) locations displayed on these channel maps. This manuscript introduces a simple application to create visualization for mutations on alpha voltage-gated sodium channels, created using the D3.js library. The application allows for mapping of variant sequences, as well as important properties like the type of variant and the phenotypes linked to the variant. It also allows for customizability and the production of high-quality images for publication. This application and code base can further be extrapolated to other ion channels as well.

neuroscience↗

bioRxiv2023

RNA sequencing demonstrates ex vivo neocortical transcriptomic changes induced by epileptiform activity in male and female mice

Seizures are generally associated with epilepsy but may also be a symptom of many other neurological conditions. A hallmark of a seizure is the intensity of the local neuronal activation, which can drive large-scale gene transcription changes. Such changes in the transcriptional profile are likely to alter neuronal function, thereby contributing to the pathological process. Therefore, there is a strong clinical imperative to characterie how gene expression is changed by seizure activity. To this end, we developed a simplified ex vivo technique for studying seizure-induced transcriptional changes. We compared the RNA sequencing profile in mouse neocortical tissue that had up to 3 hours of epileptiform activity induced by 4-aminopyridine (4AP), relative to control brain slices not exposed to the drug. We identified over 100 genes with significantly altered expression after 4AP treatment, including multiple genes involved in MAPK, TNF, and neuroinflammatory signalling pathways, all of which have been linked to epilepsy previously. Notably, the patterns in male and female brain slices were almost identical. Various immediate early genes were among those showing the largest upregulation. The set of down-regulated genes included ones that might be expected either to increase or to decrease neuronal excitability. In summary, we found the seizure-induced transcriptional profile to be complex, but the changes aligned well with an analysis of published epilepsy-associated genes. We discuss how simple models may provide new angles for investigating seizure-induced transcriptional changes. Significance StatementIt is well-established that strong neuronal activation results in large-scale transcriptomic changes. Understanding this process is of particular importance in epilepsy, which is characterized by paroxysmal pathological discharges. The complexity of in vivo activity patterns, however, present many difficulties for interpretation of the transcriptional changes. In contrast, ex vivo seizure models provide better experimental control and quantification of activity patterns, with lower welfare impact. Importantly, we now show that these models also replicate the transcriptional patterns previously reported in chronic human and animal epilepsy, thus validating their use in these kinds of study.

neuroscience↗

bioRxiv2023

Molecular pharmacology of selective NaV1.6 and dual NaV1.6 and NaV1.2 channel inhibitors that suppress excitatory neuronal activity ex vivo

Sodium channel inhibitors are used to treat neurological disorders of hyperexcitability. However, all currently available sodium channel targeting anti-seizure medications are non-selective among the NaV isoforms which potentially limits efficacy and therapeutic safety margins. XPC-7724 and XPC-5462 represent a new class of small molecule compounds. These compounds target inhibition of the NaV1.6 and NaV1.2 channels in excitatory pyramidal neurons and possess a molecular selectivity of >100 fold against NaV1.1 channels that are dominant in inhibitory cells. This profile will enable pharmacological dissection of the physiological roles of NaV1.2 and NaV1.6 and help to define the role of each channel in disease states. These compounds bind to and stabilize the inactivated-state of the channels, demonstrate higher potency with longer residency times, and slower off-rates than carbamazepine and phenytoin. These compounds possess cellular selectivity ex vivo in inhibiting action potential firing in cortical excitatory pyramidal neurons, whilst sparing fast spiking inhibitory interneurons. XPC-5462 also suppresses epileptiform activity in an ex vivo brain slice seizure model. This class of compounds provides a unique approach for treating neuronal excitability disorders by selectively down-regulating excitatory circuits. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=194 HEIGHT=200 SRC="FIGDIR/small/551643v2_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@70750corg.highwire.dtl.DTLVardef@114756aorg.highwire.dtl.DTLVardef@289009org.highwire.dtl.DTLVardef@1086e23_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2022

Pharmacological determination of the fractional block of Nav channels required to impair neuronal excitability and ex vivo seizures

Voltage-gated sodium channels (Nav) are essential for the initiation and propagation of action potentials in neurons. Of the different channel subtypes, Nav1.1, Nav1.2 and Nav1.6 are prominently expressed in the adult central nervous system (CNS). All three of these sodium channel subtypes are sensitive to block by the neurotoxin tetrodotoxin (TTX), with TTX being almost equipotent on all three subtypes. In the present study we have used TTX to determine the fractional block of Nav channels required to impair action potential firing in pyramidal neurons and reduce network seizure-like activity. Using automated patch-clamp electrophysiology, we first determined the IC50s of TTX on mouse Nav1.1, Nav1.2 and Nav1.6 channels expressed in HEK cells, demonstrating this to be consistent with previously published data on human Nav channels. We then compared this data to the potency of block of Nav current measured in pyramidal neurons from neocortical brain slices. Interestingly, we found that it requires nearly 10-fold greater concentration of TTX over the IC50 to induce significant block of action potentials using a current-step protocol. In contrast, concentrations near the IC50 resulted in a significant reduction in AP firing and increase in rheobase using a ramp protocol. Surprisingly, a 20% reduction in action potential generation observed with 3 nM TTX resulted in significant block of seizure-like activity in the 0 Mg2+ model of epilepsy. Additionally, we found that approximately 50% block in pyramidal cell intrinsic excitability is sufficient to completely block all seizure-like events. These data serve as a critical starting point in understanding how fractional block of Nav channels affect intrinsic neuronal excitability and seizure-like activity. It further suggests that seizures can be controlled without significantly compromising intrinsic neuronal activity and determines the required fold over IC50 for novel and clinically relevant Nav channel blockers to produce efficacy and limit side effects.

neuroscience↗

bioRxiv2022

Xenon LFP Analysis Platform is a Novel Graphical User Interface for Analysis of Local Field Potential from Large-Scale MEA Recordings

High-density multi-electrode array (HD-MEA) has enabled neuronal measurements at high spatial resolution to record local field potentials (LFP), extracellular spikes, and network activity with ease. Whilst we have advanced recording systems with over 4000 electrodes, capable of recording data at over 20 kHz, it still presents computational challenges to handle, process, extract, and view information from these large recordings. It can be challenging for researchers to extract and view even a single channel that has more than a billion data points, let alone process a group of channels. We have created a computational method, and an open-source toolkit built on Python, rendered on a web browser using Plotlys Dash for extracting and viewing the data, and creating interactive visualization. In addition to extracting and viewing entire or small chunks of data sampled at lower or higher frequencies, respectively, it provides a framework to collect user inputs, analyze channel groups, generate raster plots, view quick summary measures for LFP activity, detect and isolate noise channels, and generate plots and visualization in both time and frequency domain. Incorporated into our Graphical User Interface (GUI), we also have created a novel seizure detection method, which can be used to detect the onset of seizures in all or a selected group of channels and provide the following measures of seizures: distance, duration, and propagation across the region of interest. We demonstrate the utility of this toolkit, using datasets collected from the 3Brain BioCAM duplex system. For the current analysis, we demonstrate the toolkit and methods with a low sampling frequency dataset (300 Hz) and a group of approximately 400 channels. Using this toolkit, we present novel data demonstrating increased seizure propagation speed from slices of Scn1aHet mice compared to littermate controls. With advances in HD-MEA recording systems with high spatial and temporal resolution, limited tools are available for researchers to view and process these big datasets. We now provide a user-friendly toolkit to analyze LFP activity obtained from large-scale MEA recordings with translatable applications to EEG recordings, and demonstrate the utility of this new graphic user interface with novel biological findings.

neuroscience↗

bioRxiv2022

Targeting neuronal homeostasis to prevent seizures

Manipulating neuronal homeostasis, which enables neurons to regulate their intrinsic excitability, offers an attractive opportunity to prevent seizures. However, no anticonvulsant compounds have yet been reported that directly manipulate neuronal homeostasis. Here, we describe a novel class of anticonvulsant compounds, based on 4-tert-butyl-benzaldehyde (4-TBB), with a mode-of-action that includes increased expression of the homeostatic regulator Pumilio (Pum). In Drosophila and mouse we use a pentylenetetrazole (PTZ) induced seizure model, and an electrically induced seizure model for refractory seizures to evaluate anticonvulsant efficacy. The pyrazole analogue (RAB216) demonstrates best efficacy, protecting 50% of mice from PTZ-induced seizure. Knock-down of Pum, in Drosophila, blocks anticonvulsive effects, whilst analysis of validated Pum targets show significant reductions following exposure of mouse brain to 4-TBB. This study provides proof-of-principle that anticonvulsant effects can be achieved through regulation of neuronal homeostasis and identifies a chemical lead compound for future development.

neuroscience↗

bioRxiv2021

PV-specific loss of the transcriptional coactivator PGC-1α slows down the evolution of epileptic activity in an acute ictogenic model.

The transcriptional coactivator, PGC-1 (peroxisome proliferator activated receptor gamma coactivator 1), plays a key role coordinating energy requirement within cells. Its importance is reflected in the growing number of psychiatric and neurological conditions that have been associated with reduced PGC-1 levels. In cortical networks, PGC-1 is required for the induction of parvalbumin (PV) expression in interneurons, and PGC-1 deficiency affects synchronous GABAergic release. It is unknown, however, how this affects cortical excitability. We show here that knocking down PGC-1 specifically in the PV-expressing cells (PGC-1PV-/-), blocks the activity-dependent regulation of the synaptic proteins, SYT2 and CPLX1. More surprisingly, this cell-class specific knock-out of PGC-1 appears to have a novel anti-epileptic effect, as assayed in brain slices bathed in 0 Mg2+ media. The rate of pre-ictal discharges developed approximately equivalently in wild-type and PGC-1PV-/- brain slices, but the intensity of these discharges was lower in PGC-1PV-/- slices, as evident from the reduced power in the gamma range and reduced firing rates in both PV interneurons and pyramidal cells during these discharges. Reflecting this reduced intensity in the pre-ictal discharges, the PGC-1PV-/- brain slices experienced many more discharges before transitioning into a seizure-like event. Consequently, there was a large increase in the latency to the first seizure-like event in brain slices lacking PGC-1 in PV interneurons. We conclude that knocking down PGC-1 limits the range of PV interneuron firing, and this slows the pathophysiological escalation during ictogenesis.

neuroscience↗

bioRxiv2021

Synergistic positive feedback underlying seizure initiation

Seizure onset is a critically important brain state transition that has proved very difficult to predict accurately from recordings of brain activity. Here we show that an intermittent, optogenetic, stimulation paradigm reveals a latent change in dendritic excitability that is tightly correlated to the onset of seizure activity. Our data show how the precipitous nature of the transition can be understood in terms of multiple, synergistic positive feedback mechanisms: raised intracellular Cl- and extracellular K+, coupled to a reduced threshold for dendritic plateau potentials, and which in turn leads to a switch to pyramidal burst firing. Notably, the stimulation paradigm also delays the evolving epileptic activity, meaning that not only can one monitor seizure risk safely, it may even have an additional anti-epileptic benefit. One Sentence SummaryRapid transitions into seizures arise from mutually accelerating feedback loops, involving changes in dendritic excitability

neuroscience↗

bioRxiv2019

The spread of gap-junction mediated activity in neocortex is modulated by extracellular potassium

Parvalbumin-expressing interneurons in cortical networks are coupled by gap-junctions, forming a syncytium that supports propagating epileptiform discharges, induced by 4-aminopyridine. It remains unclear, however, whether these propagating events occur under more natural states, without pharmacological blockade. In particular, we investigated whether propagation also happens when extracellular K+ rises, as is known to occur following intense network activity, such as during seizures. We examined how increasing [K+]o affects the likelihood of propagating activity away from a site of focal (200-400{micro}m) optogenetic activation of PV-interneurons. Activity was recorded using a linear 16-electrode array placed along layer V of primary visual cortex. At baseline levels of [K+]o (3.5mM), induced activity was recorded only within the illuminated area. However, when [K+]o was increased above a threshold level (50th percentile= 8.0mM; interquartile range= 7.5-9.5mM), time-locked, fast-spiking unit activity, indicative of parvalbumin-expressing interneuron firing, was also recorded outside the illuminated area, propagating at 59.1 mm/s. Blockade of glutamatergic synaptic transmission reduced the efficacy of propagation, but could be restored by further increasing [K+]o. Propagation was further reduced, and in most cases prevented altogether, by pharmacological blockade of gap-junctions, achieved by any of three different drugs, quinine, mefloquine or carbenoxolone. Wash-out of quinine rapidly re-established the pattern of propagating activity. Computer simulations show qualitative differences between propagating discharges in high [K+]o and 4-aminopyridine, arising from differences in the electrotonic effects of these two manipulations. These interneuronal syncytial interactions are likely to affect the complex electrographic dynamics of seizures, once [K+]o is raised above this threshold level.\n\nSignificance statementWe demonstrate the spatially extended propagation of activity through a gap-junction mediated syncytium of parvalbumin-expressing interneurons, in conditions that are known to exist at times within the brain. Previous work has only shown gap-junction coordination very locally, through directly connected cells, or induced at a distance by pharmacological means. We show that cell-class specific spread is facilitated by raised extracellular K+. This is highly pertinent to what happens at the onset of, and during, seizures, when extracellular K+ can rise rapidly to levels well in excess of the measured threshold for propagation. Our data suggests that interneuronal coupling will be enhanced at this time, and this has clear implications for the behaviour of these cells as seizures progress.

neuroscience↗

bioRxiv2019

Divergent paths to seizure-like events.

AimMuch debate exists about how the brain transitions into an epileptic seizure. One source of confusion is that there are likely to be critical differences between experimental seizure models. To address this, we compared the evolving activity patterns in two, widely used, in vitro models of epileptic discharges.\n\nMethodsWe compared brain slices, prepared in the same way from young adult mice, that were bathed either in 0 Mg2+, or 100{micro}M 4AP, artificial cerebrospinal fluid.\n\nResultsWe find that while local field potential recordings of epileptiform discharges in the two models appear broadly similar, patch-clamp analysis reveals an important difference in the relative degree of glutamatergic involvement. 4AP affects parvalbumin-expressing interneurons more than other cortical populations, destabilizing their resting state and inducing spontaneous bursting behavior. Consequently, the most prominent pattern of transient discharge (\"interictal event\") in this model is almost purely GABAergic, although the transition to seizure-like events (SLEs) involves pyramidal recruitment. In contrast, interictal discharges in 0 Mg2+ are only maintained by a very large glutamatergic component that also involves transient discharges of the interneurons. Seizure-like events in 0 Mg2+ have significantly higher power in the high gamma frequency band (60-120Hz) than these events do in 4AP, and are greatly delayed in onset by diazepam, unlike 4AP events.\n\nConclusionsThe 0 Mg2+ and 4AP models display fundamentally different levels of glutamatergic drive, demonstrating how ostensibly similar pathological discharges can arise from different sources. We contend that similar interpretative issues will also be relevant to clinical practice.

neuroscience↗

bioRxiv2018

Region-specific differences and areal interactions underlying transitions in epileptiform activity

Understanding the nature of epileptic state transitions remains a major goal for epilepsy research. Simple in vitro models offer unique experimental opportunities, which we exploit to show that such transitions can arise from shifts in the ictal source of the activity. These transitions reflect the fact that cortical territories differ both in the type of epileptiform activity they can sustain, and their susceptibility to drug manipulation. In the zero Mg2+ model, the earliest epileptiform activity is restricted to neocortical and entorhinal networks. Hippocampal bursting only starts much later, and triggers a marked transition in neo-/entorhinal cortical activity. Thereafter, the hippocampal activity acts as a pacemaker, entraining the other territories to their discharge pattern. This entrainment persists following transection of the major axonal pathways between hippocampus and cortex, indicating that it can be mediated through a non-synaptic route. Neuronal discharges are associated with large rises in extracellular [K+], but we show that these are very localised, and therefore are not the means of entraining distant cortical areas. We conclude instead that the entrainment occurs through weak field effects distant from the pacemaker, but which are highly effective at recruiting other brain territories that are already hyperexcitable. The hippocampal epileptiform activity appears unusually susceptible to drugs that impact on K+ conductances. These findings demonstrate that the local circuitry gives rise to stereotypical epileptic activity patterns, but these are also influenced by both synaptic and non-synaptic long-range effects. Our results have important implications for our understanding of epileptic propagation, and anti-epileptic drug action.\n\nKey pointsO_LILocal neocortical and hippocampal territories show different and sterotypical patterns of acutely evolving, epileptiform activity.\nC_LIO_LINeocortical and entorhinal networks show tonic-clonic-like events, but the main hippocampal territories do not, unless it is relayed from the other areas.\nC_LIO_LITransitions in the pattern of locally recorded epileptiform activity can be indicative of a shift in the source of pathological activity, and which may spread through both synaptic and non-synaptic means.\nC_LIO_LIHippocampal epileptiform activity is promoted by 4-aminopyridine and inhibited by GABAB agonists, and appears far more sensitive to these drugs than neocortical activity.\nC_LIO_LIThese signature features of local epileptiform activity can provide useful insight into the primary source of ictal activity, aiding both experimental and clinical investigation.\nC_LI

neuroscience↗

bioRxiv2018

Human and Rodent Temporal Lobe Epilepsy is Characterized by Changes in O-GlcNAc Homeostasis that can be Reversed to Dampen Epileptiform Activity

Temporal Lobe Epilepsy (TLE) is frequently associated with changes in protein composition and post-translational modifications (PTM) that exacerbate the disorder. O-linked-{beta}-N-acetyl glucosamine (O-GlcNAc) is a PTM occurring at serine/threonine residues that integrate energy supply with demand. The enzymes O-GlcNActransferase (OGT) and O-GlcNAcase (OGA) mediate the addition and removal, respectively, of the O-GlcNAc modification. The goal of this study was to determine whether changes in OGT/OGA cycling and disruptions in protein O-GlcNAcylation occur in the epileptic hippocampus. We observed reduced global and protein specific O-GlcNAcylation and OGT expression in the kainate rat model of TLE and in human TLE hippocampal tissue. Inhibiting OGA with Thiamet-G elevated protein O-GlcNAcylation, and decreased both seizure duration and epileptic spike events, suggesting that OGA may be a therapeutic target for seizure control. These findings suggest that loss of O-GlcNAc homeostasis in the kainate model and in human TLE can be reversed via targeting of O-GlcNAc related pathways.

neuroscience↗