scholarly journals Pannexin-1 Deficiency Decreases Epileptic Activity in Mice

2020 ◽  
Vol 21 (20) ◽  
pp. 7510 ◽  
Author(s):  
Mark S. Aquilino ◽  
Paige Whyte-Fagundes ◽  
Mark K. Lukewich ◽  
Liang Zhang ◽  
Berj L. Bardakjian ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Critical Role ◽  
Epileptic Activity ◽  
Channel Blockers ◽  
Systemic Injection ◽  
Pannexin 1 ◽  
Severe Stage ◽  
Frequency Coupling ◽  
Epilepsy Models ◽  
Cross Frequency Coupling

Objective: Pannexin-1 (Panx1) is suspected of having a critical role in modulating neuronal excitability and acute neurological insults. Herein, we assess the changes in behavioral and electrophysiological markers of excitability associated with Panx1 via three distinct models of epilepsy. Methods Control and Panx1 knockout C57Bl/6 mice of both sexes were monitored for their behavioral and electrographic responses to seizure-generating stimuli in three epilepsy models—(1) systemic injection of pentylenetetrazol, (2) acute electrical kindling of the hippocampus and (3) neocortical slice exposure to 4-aminopyridine. Phase-amplitude cross-frequency coupling was used to assess changes in an epileptogenic state resulting from Panx1 deletion. Results: Seizure activity was suppressed in Panx1 knockouts and by application of Panx1 channel blockers, Brilliant Blue-FCF and probenecid, across all epilepsy models. In response to pentylenetetrazol, WT mice spent a greater proportion of time experiencing severe (stage 6) seizures as compared to Panx1-deficient mice. Following electrical stimulation of the hippocampal CA3 region, Panx1 knockouts had significantly shorter evoked afterdischarges and were resistant to kindling. In response to 4-aminopyridine, neocortical field recordings in slices of Panx1 knockout mice showed reduced instances of electrographic seizure-like events. Cross-frequency coupling analysis of these field potentials highlighted a reduced coupling of excitatory delta–gamma and delta-HF rhythms in the Panx1 knockout. Significance: These results suggest that Panx1 plays a pivotal role in maintaining neuronal hyperexcitability in epilepsy models and that genetic or pharmacological targeting of Panx1 has anti-convulsant effects.

Furosemide and Mannitol Suppression of Epileptic Activity in the Human Brain

2005 ◽  
Vol 94 (2) ◽  
pp. 907-918 ◽  
Author(s):  
Michael M. Haglund ◽  
Daryl W. Hochman
Keyword(s):  
Electrical Stimulation ◽  
Human Brain ◽  
Optical Imaging ◽  
Neuronal Excitability ◽  
Critical Role ◽  
Intractable Epilepsy ◽  
Mesial Temporal Lobe Epilepsy ◽  
Epileptic Activity ◽  
Imaging Data ◽  
Epileptiform Discharges

Most research on basic mechanisms of epilepsy and the design of new antiepileptic drugs has focused on synaptic transmission or action potential generation. However, a number of laboratory studies have suggested that nonsynaptic mechanisms, such as modulation of electric field interactions via the extracellular space (ECS), might also contribute to neuronal hypersynchrony and epileptogenicity. To date, a role for nonsynaptic modulation of epileptic activity in the human brain has not been investigated. Here we studied the effects of molecules that modulate the volume and water content of the ECS on epileptic activity in patients suffering from neocortical and mesial temporal lobe epilepsy. Electrophysiological and optical imaging data were acquired from the exposed cortices of anesthetized patients undergoing surgical treatment for intractable epilepsy. Patients were given a single intravenous injection containing either 20 mg furosemide (a cation-chloride cotransporter antagonist) or 50 g mannitol (an osmolyte). Furosemide and mannitol both significantly suppressed spontaneous epileptic spikes and electrical stimulation-evoked epileptiform discharges in all subjects, completely blocking all epileptic activity in some patients without suppressing normal electroencephalographic activity. Optical imaging suggested that the spread of electrical stimulation-evoked activity over the cortex was significantly reduced by these treatments, but the magnitude of neuronal activation near the stimulating electrode was not diminished. These results suggest that nonsynaptic mechanisms play a critical role in modulating the epileptogenicity of the human brain. Furosemide and other drugs that modulate the ECS might possess clinically useful antiepileptic properties, while avoiding the side effects associated with the suppression of neuronal excitability.

scholarly journals Thalamocortical dysrhythmia in intraoperative recordings of focal epilepsy

2019 ◽  
Vol 121 (6) ◽  
pp. 2020-2027 ◽  
Author(s):  
Daniel J. Martire ◽  
Simeon Wong ◽  
Mirriam Mikhail ◽  
Ayako Ochi ◽  
Hiroshi Otsubo ◽  
...  
Keyword(s):  
Functional Connectivity ◽  
High Frequency ◽  
Large Scale ◽  
Focal Epilepsy ◽  
Critical Role ◽  
Epileptogenic Zone ◽  
Thalamocortical Dysrhythmia ◽  
High Frequency Activity ◽  
Frequency Coupling ◽  
Cross Frequency Coupling

Resonant interactions between the thalamus and cortex subserve a critical role for maintenance of consciousness as well as cognitive functions. In states of abnormal thalamic inhibition, thalamocortical dysrhythmia (TCD) has been described. The characteristics of TCD include a slowing of resting oscillations, ectopic high-frequency activity, and increased cross-frequency coupling. Here, we demonstrate the presence of TCD in four patients who underwent resective epilepsy surgery with chronically implanted electrodes under anesthesia, continuously recording activity from brain regions at the periphery of the epileptogenic zone before and after resection. Following resection, we report an acceleration of the large-scale network resting frequency coincident with decreases in cross-frequency phase-amplitude coupling. Interregional functional connectivity in the surrounding cortex was also increased following resection of the epileptogenic focus. These findings provide evidence for the presence of TCD in focal epilepsy and highlight the importance of reciprocal thalamocortical oscillatory interactions in defining novel biomarkers for resective surgeries. NEW & NOTEWORTHY Thalamocortical dysrhythmia (TCD) occurs in the context of thalamic dysfacilitation and is characterized by slowing of resting oscillations, ectopic high-frequency activity, and cross-frequency coupling. We provide evidence for TCD in focal epilepsy by studying electrophysiological changes occurring at the periphery of the resection margin. We report acceleration of resting activity coincident with decreased cross-frequency coupling and increased functional connectivity. The study of TCD in epilepsy has implications as a biomarker and therapeutic target.

scholarly journals PKA-RIIβ autophosphorylation modulates PKA activity and seizure phenotypes in mice

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Jingliang Zhang ◽  
Chenyu Zhang ◽  
Xiaoling Chen ◽  
Bingwei Wang ◽  
Weining Ma ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Neurological Disorders ◽  
Neuronal Excitability ◽  
Granule Cells ◽  
Critical Role ◽  
Intrinsic Excitability ◽  
Seizure Susceptibility ◽  
Seizure Onset ◽  
Potential Therapeutic Target ◽  
Seizure Model

AbstractTemporal lobe epilepsy (TLE) is one of the most common and intractable neurological disorders in adults. Dysfunctional PKA signaling is causally linked to the TLE. However, the mechanism underlying PKA involves in epileptogenesis is still poorly understood. In the present study, we found the autophosphorylation level at serine 114 site (serine 112 site in mice) of PKA-RIIβ subunit was robustly decreased in the epileptic foci obtained from both surgical specimens of TLE patients and seizure model mice. The p-RIIβ level was negatively correlated with the activities of PKA. Notably, by using a P-site mutant that cannot be autophosphorylated and thus results in the released catalytic subunit to exert persistent phosphorylation, an increase in PKA activities through transduction with AAV-RIIβ-S112A in hippocampal DG granule cells decreased mIPSC frequency but not mEPSC, enhanced neuronal intrinsic excitability and seizure susceptibility. In contrast, a reduction of PKA activities by RIIβ knockout led to an increased mIPSC frequency, a reduction in neuronal excitability, and mice less prone to experimental seizure onset. Collectively, our data demonstrated that the autophosphorylation of RIIβ subunit plays a critical role in controlling neuronal and network excitabilities by regulating the activities of PKA, providing a potential therapeutic target for TLE.

scholarly journals Delta-mediated cross-frequency coupling organizes oscillatory activity across the rat cortico-basal ganglia network

2013 ◽  
Vol 7 ◽  
Author(s):  
Jon López-Azcárate ◽  
María Jesús Nicolás ◽  
Ivan Cordon ◽  
Manuel Alegre ◽  
Miguel Valencia ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Oscillatory Activity ◽  
Frequency Coupling ◽  
Cross Frequency Coupling

scholarly journals Gamma Oscillations and Their Cross-frequency Coupling in the Primate Hippocampus during Sleep

SLEEP ◽  
2015 ◽  
Vol 38 (7) ◽  
pp. 1085-1091 ◽  
Author(s):  
Saori Takeuchi ◽  
Tatsuya Mima ◽  
Rie Murai ◽  
Hideki Shimazu ◽  
Yoshikazu Isomura ◽  
...  
Keyword(s):  
Gamma Oscillations ◽  
Frequency Coupling ◽  
Cross Frequency Coupling

scholarly journals Working Memory and Cross-Frequency Coupling of Neuronal Oscillations

2021 ◽  
Vol 12 ◽  
Author(s):  
Mohammed Abubaker ◽  
Wiam Al Qasem ◽  
Eugen Kvašňák
Keyword(s):  
Working Memory ◽  
Cognitive Impairment ◽  
Brain Stimulation ◽  
Large Body ◽  
Cognitive Outcomes ◽  
Essential Component ◽  
Non Invasive ◽  
Transcranial Alternating Current Stimulation ◽  
Frequency Coupling ◽  
Cross Frequency Coupling

Working memory (WM) is the active retention and processing of information over a few seconds and is considered an essential component of cognitive function. The reduced WM capacity is a common feature in many diseases, such as schizophrenia, attention deficit hyperactivity disorder (ADHD), mild cognitive impairment (MCI), and Alzheimer's disease (AD). The theta-gamma neural code is an essential component of memory representations in the multi-item WM. A large body of studies have examined the association between cross-frequency coupling (CFC) across the cerebral cortices and WM performance; electrophysiological data together with the behavioral results showed the associations between CFC and WM performance. The oscillatory entrainment (sensory, non-invasive electrical/magnetic, and invasive electrical) remains the key method to investigate the causal relationship between CFC and WM. The frequency-tuned non-invasive brain stimulation is a promising way to improve WM performance in healthy and non-healthy patients with cognitive impairment. The WM performance is sensitive to the phase and rhythm of externally applied stimulations. CFC-transcranial-alternating current stimulation (CFC-tACS) is a recent approach in neuroscience that could alter cognitive outcomes. The studies that investigated (1) the association between CFC and WM and (2) the brain stimulation protocols that enhanced WM through modulating CFC by the means of the non-invasive brain stimulation techniques have been included in this review. In principle, this review can guide the researchers to identify the most prominent form of CFC associated with WM processing (e.g., theta/gamma phase-amplitude coupling), and to define the previously published studies that manipulate endogenous CFC externally to improve WM. This in turn will pave the path for future studies aimed at investigating the CFC-tACS effect on WM. The CFC-tACS protocols need to be thoroughly studied before they can be considered as therapeutic tools in patients with WM deficits.

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