Enhanced excitability of the hippocampal CA2 region and its contribution to seizure activity in a mouse model of temporal lobe epilepsy

Neuron, Год журнала: 2022, Номер 110(19), С. 3121 - 3138.e8

Опубликована: Авг. 19, 2022

Язык: Английский

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Acetylcholine receptor based chemogenetics engineered for neuronal inhibition and seizure control assessed in mice

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Янв. 18, 2024

Abstract Epilepsy is a prevalent disorder involving neuronal network hyperexcitability, yet existing therapeutic strategies often fail to provide optimal patient outcomes. Chemogenetic approaches, where exogenous receptors are expressed in defined brain areas and specifically activated by selective agonists, appealing methods constrain overactive activity. We developed BARNI (Bradanicline- Acetylcholine-activated Receptor for Neuronal Inhibition), an engineered channel comprised of the α7 nicotinic acetylcholine receptor ligand-binding domain coupled α1 glycine anion pore domain. Here we demonstrate that activation clinical stage receptor-selective agonist bradanicline effectively suppressed targeted activity, controlled both acute chronic seizures male mice. Our results evidence use inhibitory acetylcholine-based activatable endogenous agonists as potential approach treating epilepsy.

Язык: Английский

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Optimization of closed-loop electrical stimulation enables robust cerebellar-directed seizure control

Brain, Год журнала: 2022, Номер 146(1), С. 91 - 108

Опубликована: Фев. 5, 2022

Additional treatment options for temporal lobe epilepsy are needed, and potential interventions targeting the cerebellum of interest. Previous animal work has shown strong inhibition hippocampal seizures through on-demand optogenetic manipulation cerebellum. However, decades examining electrical stimulation-a more immediately translatable approach-targeting produced very mixed results. We were therefore interested in exploring impact that stimulation parameters may have on seizure outcomes. Using a mouse model epilepsy, we conducted cerebellar cortex, varied charge, frequency pulse width, resulting over 1000 different combinations settings. To explore this parameter space an efficient, data-driven, manner, utilized Bayesian optimization with Gaussian process regression, implemented MATLAB Expected Improvement Plus acquisition function. examined three fitting conditions two electrode orientations. Following process, additional experiments to test effectiveness selected Regardless experimental setup, found allowed identification effective intervention Additionally, generally similar optimal settings identified across animals, suggesting personalized not always be necessary. While effective, predicted from regression ineffective failed provide control. Taken together, our results blueprint exploration large control illustrate robust can achieved cerebellum, but only if correct used.

Язык: Английский

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Interictal spikes in Alzheimer's disease: Preclinical evidence for dominance of the dentate gyrus and cholinergic control by the medial septum

Neurobiology of Disease, Год журнала: 2023, Номер 187, С. 106294 - 106294

Опубликована: Сен. 13, 2023

Interictal spikes (IIS) are a common type of abnormal electrical activity in Alzheimer's disease (AD) and preclinical models. The brain regions where IIS largest not known but important because such data would suggest sites that contribute to generation. Because hippocampus cortex exhibit altered excitability AD models, we asked which areas dominate the during along cortical-CA1-dentate gyrus (DG) dorso-ventral axis. medial septal (MS) cholinergic neurons overactive when typically occur, also tested novel hypothesis silencing MS selectively reduce IIS. We used mice simulate aspects AD: Tg2576 mice, presenilin 2 (PS2) knockout Ts65Dn mice. To silence neurons, were bred with choline-acetyltransferase (ChAT)-Cre offspring injected AAV encoding inhibitory designer receptors exclusively activated by drugs (DREADDs). recorded local field potentials cortical-CA1-DG axis using silicon probes wakefulness, slow-wave sleep (SWS) rapid eye movement (REM) sleep. detected all transgenic or age-matched controls. detectable throughout occurred primarily REM In 3 mouse lines, amplitudes significantly greater DG granule cell layer vs. CA1 pyramidal overlying cortex. Current source density analysis showed robust early current sources DG, additional also. Selective chemogenetic reduced rate without affecting overall duration, number bouts, latency sleep, theta power REM. Notably, two control interventions no effects. Consistent maximal amplitude strong is remarkably active addition, reducing tone, at times hyperactive, could be new strategy AD.

Язык: Английский

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Increased Dentate Gyrus Excitability in the Intrahippocampal Kainic Acid Mouse Model for Temporal Lobe Epilepsy

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(1), С. 660 - 660

Опубликована: Янв. 4, 2024

The intrahippocampal kainic acid (IHKA) mouse model is an extensively used in vivo to investigate the pathophysiology of mesial temporal lobe epilepsy (mTLE) and develop novel therapies for drug-resistant epilepsy. It characterized by profound hippocampal sclerosis spontaneously occurring seizures with a major role injected damaged hippocampus, but little known about excitability specific subregions. purpose this study was electrophysiologically characterize subregions chronic phase induced IHKA model. We recorded field postsynaptic potentials (fPSPs) after electrical stimulation CA1 region dentate gyrus (DG) slices healthy mice using multielectrode array (MEA). In DG, significantly steeper fPSP slope found, reflecting higher synaptic strength. Population spikes were more prevalent larger spatial distribution group, degree granule cell output. Only minor differences found region. These results point increased neuronal DG not hippocampus mice. This method, which from investigated MEA, can now be further explored as potential new screen interventions that restore function potentially lead mTLE.

Язык: Английский

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Involvement of the contralateral hippocampus in ictal‐like but not interictal epileptic activities in the kainate mouse model of temporal lobe epilepsy

Epilepsia, Год журнала: 2024, Номер 65(7), С. 2082 - 2098

Опубликована: Май 17, 2024

Animal and human studies have shown that the seizure-generating region is vastly dependent on distant neuronal hubs can decrease duration propagation of ongoing seizures. However, we still lack a comprehensive understanding impact brain areas specific interictal ictal epileptic activities (e.g., isolated spikes, spike trains, seizures). Such knowledge critically needed, because all kinds are not equivalent in terms clinical expression progression disease.

Язык: Английский

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High‐frequency oscillations (250–500 Hz) in animal models of Alzheimer's disease and two animal models of epilepsy

Epilepsia, Год журнала: 2022, Номер 64(1), С. 231 - 246

Опубликована: Ноя. 8, 2022

To test the hypothesis that high-frequency oscillations (HFOs) between 250 and 500 Hz occur in mouse models of Alzheimer's disease (AD) thus are not unique to epilepsy.

Язык: Английский

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Sex and Estrous Cycle Stage Shape Left-Right Asymmetry in Chronic Hippocampal Seizures in Mice

eNeuro, Год журнала: 2023, Номер 10(6), С. ENEURO.0041 - 23.2023

Опубликована: Май 29, 2023

Lateralization of hippocampal function is indicated by varied outcomes patients with neurologic disorders that selectively affect one hemisphere this structure, such as temporal lobe epilepsy (TLE). The intrahippocampal kainic acid (IHKA) injection model TLE allows for targeted damage to the left or right hippocampus, enabling systematic comparison effects left-right asymmetry on seizure and nonseizure outcomes. Although varying phenotypic based side in dorsal hippocampus were recently evaluated model, differences chronic patterns left- (IHKA-L) versus right-injected (IHKA-R) IHKA animals have yet be evaluated. Here, we assessed incidence male female IHKA-L IHKA-R mice. Females displayed increased electrographic activity compared males at both two four months postinjection. In addition, females showed higher frequency than diestrus estrus postinjection, but duration percent time seizures only diestrus. These cycle stage-associated changes, however, did not persist Furthermore, lateralized difference burden was observed males. results indicate first can shape burden. Overall, these demonstrate a female-specific interact estrous stage mice epilepsy, implications neural behavior normal disease states.

Язык: Английский

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Hippocampal area CA2 controls seizure dynamics, interictal EEG abnormalities and social comorbidity in mouse models of temporal lobe epilepsy

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Янв. 19, 2023

Temporal lobe epilepsy (TLE) is characterized by spontaneous recurrent seizures, abnormal activity between and impaired behavior. CA2 pyramidal neurons (PNs) are potentially important because inhibiting them with a chemogenetic approach reduces seizure frequency in mouse model of TLE. However, whether seizures could be stopped timing inhibition just as begins unclear. Furthermore, would reduce the cortical motor manifestations not clear. Finally, interictal EEG abnormalities TLE comorbidities improved unknown. Therefore, real-time optogenetic silencing PNs during behavior were studied 2 models significantly reduced duration time spent convulsive Interictal spikes high oscillations reduced, social was improved. brief focal their propagation, manifestations, improves EEG, ameliorates comorbidities.Real-time at onset durationWhen hippocampus it also seizuresInterictal silencingReal-time (>250Hz) rescues memory deficits chronic epileptic mice.

Язык: Английский

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Ligand-gated mechanisms leading to ictogenesis in focal epileptic disorders

Neurobiology of Disease, Год журнала: 2023, Номер 180, С. 106097 - 106097

Опубликована: Март 25, 2023

We review here the neuronal mechanisms that cause seizures in focal epileptic disorders and, specifically, those involving limbic structures are known to be implicated human mesial temporal lobe epilepsy. In both patients and animal models, initiation of - which most often characterized by a low-voltage fast onset EEG pattern is presumably dependent on synchronous firing GABA-releasing interneurons that, activating post-synaptic GABAA receptors, large increases extracellular [K+] through activation co-transporter KCC2. A similar mechanism may contribute seizure maintenance; accordingly, inhibiting KCC2 activity transforms into continuous short-lasting epileptiform discharges. It has also been found interactions between different areas system modulate occurrence controlling homeostasis. line with this view, low-frequency electrical or optogenetic networks restrain generation, an effect involve GABAB receptors activity-dependent changes synchronization. Overall, these findings highlight paradoxical role signaling generation maintenance, emphasize efficacy abating seizures, provide experimental evidence explaining poor antiepileptic drugs designed augment GABAergic function disorders.

Язык: Английский

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