scholarly journals Impaired State-Dependent Potentiation of GABAergic Synaptic Currents Triggers Seizures in a Genetic Generalized Epilepsy Model

2020 ◽  
Author(s):  
Chun-Qing Zhang ◽  
Mackenzie A Catron ◽  
Li Ding ◽  
Caitlyn M Hanna ◽  
Martin J Gallagher ◽  
...  
Keyword(s):  
Slow Wave ◽  
Cortical Neurons ◽  
Slow Wave Sleep ◽  
Brain Slices ◽  
Epileptic Activity ◽  
Epilepsy Syndrome ◽  
Synaptic Currents ◽  
State Dependent ◽  
Generalized Epilepsy

Abstract Epileptic activity in genetic generalized epilepsy (GGE) patients preferentially appears during sleep and its mechanism remains unknown. Here, we found that sleep-like slow-wave oscillations (0.5 Hz SWOs) potentiated excitatory and inhibitory synaptic currents in layer V cortical pyramidal neurons from wild-type (wt) mouse brain slices. In contrast, SWOs potentiated excitatory, but not inhibitory, currents in cortical neurons from a heterozygous (het) knock-in (KI) Gabrg2+Q/390X model of Dravet epilepsy syndrome. This created an imbalance between evoked excitatory and inhibitory currents to effectively prompt neuronal action potential firings. Similarly, physiologically similar up-/down-state induction (present during slow-wave sleep) in cortical neurons also potentiated excitatory synaptic currents within brain slices from wt and het KI mice. Moreover, this state-dependent potentiation of excitatory synaptic currents entailed some signaling pathways of homeostatic synaptic plasticity. Consequently, in het KI mice, in vivo SWO induction (using optogenetic methods) triggered generalized epileptic spike-wave discharges (SWDs), being accompanied by sudden immobility, facial myoclonus, and vibrissa twitching. In contrast, in wt littermates, SWO induction did not cause epileptic SWDs and motor behaviors. To our knowledge, this is the first mechanism to explain why epileptic SWDs preferentially happen during non rapid eye-movement sleep and quiet-wakefulness in human GGE patients.

scholarly journals Impaired state-dependent potentiation of GABAergic synaptic currents triggers seizures in an idiopathic generalized epilepsy model

2020 ◽  
Author(s):  
Chun-Qing Zhang ◽  
Mackenzie A. Catron ◽  
Li Ding ◽  
Caitlyn M. Hanna ◽  
Martin J. Gallagher ◽  
...  
Keyword(s):  
Slow Wave ◽  
Cortical Neurons ◽  
Pyramidal Neurons ◽  
Slow Wave Sleep ◽  
Ex Vivo ◽  
Brain Slices ◽  
Idiopathic Generalized Epilepsy ◽  
Synaptic Currents ◽  
Generalized Epilepsy

AbstractIdiopathic generalized epilepsy(IGE) patients have genetic causes and their seizure onset mechanisms particularly during sleep remain elusive. Here we proposed that sleep-like slow-wave oscillations(0.5 Hz SWOs) potentiated excitatory or inhibitory synaptic currents in layer V cortical pyramidal neurons from wild-type(wt) mouse ex vivo brain slices. In contrast, SWOs potentiated excitatory, not inhibitory, currents in cortical neurons from heterozygous(het) knock-in(KI) IGE mice(GABAA receptor γ2 subunit Gabrg2Q390X mutation), creating an imbalance between evoked excitatory and inhibitory currents to effectively prompt neuronal action potentials. Similarly, more physiologically similar up/down-state(present during slow-wave sleep) induction in cortical neurons could potentiate excitatory synaptic currents within slices from wt/het Gabrg2Q390X KI mice. Consequently, SWOs or up/down-state induction in vivo (using optogenetic method) could trigger epileptic spike-wave discharges(SWDs) in het Gabrg2Q390X KI mice. To our knowledge, this is the first operative mechanism to explain why epileptic SWDs preferentially happen during non-REM sleep or quiet-wakefulness in human IGE patients.

Short-Duration Epileptic Discharges Show a Distinct Phase Preference During Ongoing Hippocampal Slow Oscillations

2010 ◽  
Vol 104 (4) ◽  
pp. 2194-2202 ◽  
Author(s):  
Philip H. de Guzman ◽  
Farhang Nazer ◽  
Clayton T. Dickson
Keyword(s):  
Short Duration ◽  
Temporal Lobe ◽  
Slow Wave ◽  
Rem Sleep ◽  
Slow Wave Sleep ◽  
Epileptiform Activity ◽  
Epileptic Activity ◽  
Network Synchronization ◽  
State Dependent ◽  
Oscillatory Pattern

Non-REM (slow-wave) sleep has been shown to facilitate temporal lobe epileptiform events, whereas REM sleep seems more restrictive. This state-dependent modulation may be the result of the enhancement of excitatory synaptic transmission and/or the degree of network synchronization expressed within the hippocampus of the temporal lobe. The slow oscillation (SO), a ∼1 Hz oscillatory pattern expressed during non-REM sleep and urethane anesthesia, has been recently shown to facilitate the generation, maintenance, and propagation of stimulus-evoked epileptiform activity in the hippocampus. To further address the state-dependent modulation of epileptic activity during the SO, we studied the properties of short-duration interictal-like activity generated by focal application of penicillin in the hippocampus of urethane-anesthetized rats. Epileptiform spikes were larger but only slightly more prevalent during the SO as opposed to the theta (REM-like) state. More notably, however, epileptic spikes had a significant tendency to occur just following the peak negativity of ongoing SO cycles. Because of the known phase-dependent changes in 1) synaptic excitability (just following the positive peak of the SO) and 2) network synchronization (during the negative peak of the SO), these results suggest that it is the synchrony and not the changes in synaptic excitability that lead to the facilitation of epileptiform activity during sleep-like slow wave states.

scholarly journals Physiological Properties of Raphe Magnus Neurons During Sleep and Waking

1999 ◽  
Vol 81 (2) ◽  
pp. 584-595 ◽  
Author(s):  
Cynthia G. Leung ◽  
Peggy Mason
Keyword(s):  
Slow Wave ◽  
Slow Wave Sleep ◽  
Noxious Heat ◽  
Somatosensory Stimulation ◽  
Nociceptive Transmission ◽  
Cell Discharge ◽  
Descending Modulation ◽  
State Dependent ◽  
Physiological Properties ◽  
Raphe Magnus

Physiological properties of raphe magnus neurons during sleep and waking. Neurons in the medullary raphe magnus (RM) that are important in the descending modulation of nociceptive transmission are classified by their response to noxious tail heat as on,off, or neutral cells. Experiments in anesthetized animals demonstrate that RM on cells facilitate and off cells inhibit nociceptive transmission. Yet little is known of the physiology of these cells in the unanesthetized animal. The first aim of the present experiments was to determine whether cells with on- and off-like responses to noxious heat exist in the unanesthetized rat. Second, to determine if RM cells have state-dependent discharge, the activity of RM neurons was recorded during waking and sleeping states. Noxious heat applied during waking and slow wave sleep excited one group of cells (on-u) in unanesthetized rats. Other cells were inhibited by noxious heat (off-u) applied during waking and slow wave sleep states in unanesthetized rats. Neutral-u cells did not respond to noxious thermal stimulation applied during either slow wave sleep or waking. On-u and off-u cells were more likely to respond to noxious heat during slow wave sleep than during waking and were least likely to respond when the animal was eating or drinking. Although RM cells rarely respond to innocuous stimulation applied during anesthesia, on-u andoff-u cells were excited and inhibited, respectively, by innocuous somatosensory stimulation in the unanesthetized rat. The spontaneous activity of >90% of the RM neurons recorded in the unanesthetized rat was influenced by behavioral state. Off-u cells discharged sporadically during waking but were continuously active during slow wave sleep. By contrast,on-u and neutral-u cells discharged in bursts during waking and either ceased to discharge entirely or discharged at a low rate during slow wave sleep. We suggest that off cell discharge functions to suppress pain-evoked reactions during sleep, whereas on cell discharge facilitates pain-evoked responses during waking.

scholarly journals Selective corticostriatal plasticity during acquisition of an auditory discrimination task

2014 ◽  
Author(s):  
Qiaojie Xiong ◽  
Petr Znamenskiy ◽  
Anthony Zador
Keyword(s):  
Cortical Neurons ◽  
Brain Slices ◽  
Frequency Discrimination ◽  
Auditory Discrimination ◽  
Low Frequencies ◽  
Reward Contingencies ◽  
Corticostriatal Plasticity

Perceptual decisions are based on the activity of sensory cortical neurons, but how organisms learn to transform this activity into appropriate actions remains unknown. Projections from the auditory cortex to the auditory striatum carry information that drives decisions in an auditory frequency discrimination task1. To assess the role of these projections in learning, we developed a Channelrhodopsin-2-based assay to selectively probe for synaptic plasticity associated with corticostriatal neurons representing different frequencies. Here we report that learning this auditory discrimination preferentially potentiates corticostriatal synapses from neurons representing either high or low frequencies, depending on reward contingencies. We observed frequency-dependent corticostriatal potentiation in vivo over the course of training, and in vitro in striatal brain slices. Our findings suggest a model in which selective potentiation of inputs representing different components of a sensory stimulus enables the learned transformation of sensory input into actions.

Low-Calcium Epileptiform Activity in the Hippocampus In Vivo

2003 ◽  
Vol 90 (4) ◽  
pp. 2253-2260 ◽  
Author(s):  
Zhouyan Feng ◽  
Dominique M. Durand
Keyword(s):  
Synaptic Transmission ◽  
Epileptiform Activity ◽  
Brain Slices ◽  
Early Period ◽  
Epileptic Activity ◽  
Slow Waves ◽  
Stratum Radiatum ◽  
Low Calcium

It has been clearly established that nonsynaptic interactions are sufficient for generating epileptiform activity in brain slices. However, it is not known whether this type of epilepsy model can be generated in vivo. In this paper we investigate low-calcium nonsynaptic epileptiform activity in an intact hippocampus. The calcium chelator EGTA was used to lower [Ca2+]o in the hippocampus of urethane anesthetized rats. Spontaneous and evoked field potentials in CA1 pyramidal stratum and in CA1 stratum radiatum were recorded using four-channel silicon recording probes. Three different types of epileptic activity were observed while synaptic transmission was gradually blocked by a decline in hippocampal [Ca2+]o. A short latency burst, named early-burst, occurred during the early period of EGTA application. Periodic slow-waves and a long latency high-frequency burst, named late-burst, were seen after synaptic transmission was mostly blocked. Therefore these activities appear to be associated with nonsynaptic mechanisms. Moreover, the slow-waves were similar in appearance to the depolarization potential shifts in vitro with low calcium. In addition, excitatory postsynaptic amino acid antagonists could not eliminate the development of slow-waves and late-bursts. The slow-waves and late-bursts were morphologically similar to electrographic seizure activity seen in patients with temporal lobe epilepsy. These results clearly show that epileptic activity can be generated in vivo in the absence of synaptic transmission. This type of low-calcium nonsynaptic epilepsy model in an intact hippocampus could play an important role in revealing additional mechanisms of epilepsy disorders and in developing novel anti-convulsant drugs.

scholarly journals Activity-Dependent Downscaling of Subthreshold Synaptic Inputs during Slow-Wave-Sleep-like Activity In Vivo

Neuron ◽  
2018 ◽  
Vol 97 (6) ◽  
pp. 1244-1252.e5 ◽  
Author(s):  
Ana González-Rueda ◽  
Victor Pedrosa ◽  
Rachael C. Feord ◽  
Claudia Clopath ◽  
Ole Paulsen
Keyword(s):  
Slow Wave ◽  
Slow Wave Sleep ◽  
Synaptic Inputs ◽  
Activity Dependent

Olanzapine increases slow-wave sleep: evidence for blockade of central 5-HT2C receptors in vivo

2000 ◽  
Vol 47 (5) ◽  
pp. 468-470 ◽  
Author(s):  
Ann L Sharpley ◽  
Catherine M Vassallo ◽  
Philip J Cowen
Keyword(s):  
Slow Wave ◽  
Slow Wave Sleep

scholarly journals Sleep slow-wave oscillations trigger seizures in a genetic epilepsy model of Dravet syndrome

2022 ◽  
Author(s):  
Mackenzie A. Catron ◽  
Rachel K. Howe ◽  
Gai-Linn K. Besing ◽  
Emily K. St. John ◽  
Cobie Victoria Potesta ◽  
...  
Keyword(s):  
Slow Wave ◽  
Epileptic Seizures ◽  
Nrem Sleep ◽  
Dravet Syndrome ◽  
Brain State ◽  
Synaptic Potentiation ◽  
Sleep Period ◽  
State Dependent ◽  
Slow Wave Oscillations

Sleep is the brain state when cortical activity decreases and memory consolidates. However, in human epileptic patients, including genetic epileptic seizures such as Dravet syndrome, sleep is the preferential period when epileptic spike-wave discharges (SWDs) appear, with more severe epileptic symptoms in female patients than male patients, which influencing patient sleep quality and memory. Currently, seizure onset mechanisms during sleep period still remain unknown. Our previous work has shown that the sleep-like state-dependent synaptic potentiation mechanism can trigger epileptic SWDs (Zhang et al., 2021). In this study, using one heterozygous (het) knock-in (KI) transgenic mice (GABAA receptor γ2 subunit Gabrg2Q390X mutation) and an optogenetic method, we hypothesized that slow-wave oscillations (SWOs) themselves in vivo could trigger epileptic seizures. We found that epileptic SWDs in het Gabrg2+/Q390X KI mice exhibited preferential incidence during NREM sleep period, accompanied by motor immobility/ facial myoclonus/vibrissal twitching, with more frequent incidence in female het KI mice than male het KI mice. Optogenetic induced SWOs in vivo significantly increased epileptic seizure incidence in het Gabrg2+/Q390X KI mice with increased duration of NREM sleep or quiet-wakeful states. Furthermore, suppression of SWO-related homeostatic synaptic potentiation by 4-(diethylamino)-benzaldehyde (DEAB) injection (i.p.) greatly decreased seizure incidence in het KI mice, suggesting that SWOs did trigger seizure activity in het KI mice. In addition, EEG delta-frequency (0.1-4 Hz) power spectral density during NREM sleep was significantly larger in female het Gabrg2+/Q390X KI mice than male het Gabrg2+/Q390X KI mice, which likely contributes to the gender difference in seizure incidence during NREM sleep/quiet-wake as that in human patients.

scholarly journals Breakdown of Effective Connectivity During Slow Wave Sleep: Investigating the Mechanism Underlying a Cortical Gate Using Large-Scale Modeling

2009 ◽  
Vol 102 (4) ◽  
pp. 2096-2111 ◽  
Author(s):  
Steve K. Esser ◽  
Sean Hill ◽  
Giulio Tononi
Keyword(s):  
Slow Wave ◽  
Large Scale ◽  
Slow Wave Sleep ◽  
Effective Connectivity ◽  
Signal Transmission ◽  
Sensory Stimulation ◽  
Scale Model ◽  
Synaptic Excitation ◽  
Cortical Areas

Effective connectivity between cortical areas decreases during slow wave sleep. This decline can be observed in the reduced interareal propagation of activity evoked either directly in cortex by transcranial magnetic stimulation (TMS) or by sensory stimulation. We present here a large-scale model of the thalamocortical system that is capable of reproducing these experimental observations. This model was constructed according to a large number of physiological and anatomical constraints and includes over 30,000 spiking neurons interconnected by more than 5 million synaptic connections and organized into three cortical areas. By simulating the different effects of arousal promoting neuromodulators, the model can produce a waking or a slow wave sleep-like mode. In this work, we also seek to explain why intercortical signal transmission decreases in slow wave sleep. The traditional explanation for reduced brain responses during this state, a thalamic gate, cannot account for the reduced propagation between cortical areas. Therefore we propose that a cortical gate is responsible for this diminished intercortical propagation. We used our model to test three candidate mechanisms that might produce a cortical gate during slow wave sleep: a propensity to enter a local down state following perturbation, which blocks the propagation of activity to other areas, increases in potassium channel conductance that reduce neuronal responsiveness, and a shift in the balance of synaptic excitation and inhibition toward inhibition, which decreases network responses to perturbation. Of these mechanisms, we find that only a shift in the balance of synaptic excitation and inhibition can account for the observed in vivo response to direct cortical perturbation as well as many features of spontaneous sleep.

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