High-Frequency Network Activity, Global Increase in Neuronal Activity, and Synchrony Expansion Precede Epileptic Seizures In Vitro

Understanding the impact of active dendritic properties on network activity in vivo has so far been restricted to studies in anesthetized animals. However, to date no study has been made to determine the direct effect of the anesthetics themselves on dendritic properties. Here, we investigated the effects of three types of anesthetics commonly used for animal experiments (urethane, pentobarbital and ketamine/xylazine). We investigated the generation of calcium spikes, the propagation of action potentials (APs) along the apical dendrite and the somatic firing properties in the presence of anesthetics in vitro using dual somatodendritic whole cell recordings. Calcium spikes were evoked with dendritic current injection and high-frequency trains of APs at the soma. Surprisingly, we found that the direct actions of anesthetics on calcium spikes were very different. Two anesthetics (urethane and pentobarbital) suppressed dendritic calcium spikes in vitro, whereas a mixture of ketamine and xylazine enhanced them. Propagation of spikes along the dendrite was not significantly affected by any of the anesthetics but there were various changes in somatic firing properties that were highly dependent on the anesthetic. Last, we examined the effects of anesthetics on calcium spike initiation and duration in vivo using high-frequency trains of APs generated at the cell body. We found the same anesthetic-dependent direct effects in addition to an overall reduction in dendritic excitability in anesthetized rats with all three anesthetics compared with the slice preparation.

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Spike Timing of Lacunosom-Moleculare Targeting Interneurons and CA3 Pyramidal Cells During High-Frequency Network Oscillations In Vitro

Journal of Neurophysiology ◽

10.1152/jn.00188.2007 ◽

2007 ◽

Vol 98 (1) ◽

pp. 96-104 ◽

Cited By ~ 20

Author(s):

Jay Spampanato ◽

Istvan Mody

Keyword(s):

High Frequency ◽

Epileptiform Activity ◽

Field Potential ◽

Pyramidal Cells ◽

Gamma Oscillations ◽

Spike Timing ◽

Network Activity ◽

Network Oscillations ◽

Ca3 Pyramidal Cells

Network activity in the 200- to 600-Hz range termed high-frequency oscillations (HFOs) has been detected in epileptic tissue from both humans and rodents and may underlie the mechanism of epileptogenesis in experimental rodent models. Slower network oscillations including theta and gamma oscillations as well as ripples are generated by the complex spike timing and interactions between interneurons and pyramidal cells of the hippocampus. We determined the activity of CA3 pyramidal cells, stratum oriens lacunosum-moleculare (O-LM) and s. radiatum lacunosum-moleculare (R-LM) interneurons during HFO in the in vitro low-Mg2+ model of epileptiform activity in GIN mice. In these animals, interneurons can be identified prior to cell-attached recordings by the expression of green-fluorescent protein (GFP). Simultaneous local field potential recordings from s. pyramidale and on-cell recordings of individual interneurons and principal cells revealed three primary firing behaviors of the active cells: 36% of O-LM interneurons and 60% of pyramidal cells fired action potentials at high frequencies during the HFO. R-LM interneurons were biphasic in that they fired at high frequency at the beginning of the HFO but stopped firing before its end. When considering only the highest frequency component of the oscillations most pyramidal cells fired on the rising phase of the oscillation. These data provide evidence for functional distinction during HFOs within otherwise homogeneous groups of O-LM interneurons and pyramidal cells.

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Dynamics of high-frequency synchronization during seizures

Journal of Neurophysiology ◽

10.1152/jn.00761.2012 ◽

2013 ◽

Vol 109 (10) ◽

pp. 2423-2437 ◽

Cited By ~ 7

Author(s):

Giri P. Krishnan ◽

Gregory Filatov ◽

Maxim Bazhenov

Keyword(s):

High Frequency ◽

Epileptiform Activity ◽

Epileptic Seizures ◽

Temporal Analysis ◽

Neuronal Firing ◽

Extracellular Potassium ◽

Epileptiform Discharges ◽

Baseline Activity ◽

High Frequency Activity

Pathological synchronization of neuronal firing is considered to be an inherent property of epileptic seizures. However, it remains unclear whether the synchrony increases for the high-frequency multiunit activity as well as for the local field potentials (LFPs). We present spatio-temporal analysis of synchronization during epileptiform activity using wide-band (up to 2,000 Hz) spectral analysis of multielectrode array recordings at up to 60 locations throughout the mouse hippocampus in vitro. Our study revealed a prominent structure of LFP profiles during epileptiform discharges, triggered by elevated extracellular potassium, with characteristic distribution of current sinks and sources with respect to anatomical structure. The cross-coherence of high-frequency activity (500–2,000 Hz) across channels was reduced during epileptic bursts compared with baseline activity and showed the opposite trend for lower frequencies. Furthermore, the magnitude of cross-coherence during epileptiform activity was dependent on distance: electrodes closer to the epileptic foci showed increased cross-coherence and electrodes further away showed reduced cross-coherence for high-frequency activity. These experimental observations were re-created and supported in a computational model. Our study suggests that different intrinsic and synaptic processes can mediate paroxysmal synchronization at low, medium, and high frequencies.

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Sex-Specific Cannabidiol- and Iloperidone-Induced Neuronal Activity Changes in an In Vitro MAM Model System of Schizophrenia

International Journal of Molecular Sciences ◽

10.3390/ijms22115511 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5511

Author(s):

Rachel-Karson Thériault ◽

Myles St-Denis ◽

Tristen Hewitt ◽

Jibran Y. Khokhar ◽

Jasmin Lalonde ◽

...

Keyword(s):

Drug Interactions ◽

Neuronal Activity ◽

Underlying Mechanism ◽

Network Activity ◽

Antipsychotic Therapy ◽

Sex Effects ◽

Activity Measurements ◽

Cortical Circuit ◽

Bursting Activity

Cortical circuit dysfunction is thought to be an underlying mechanism of schizophrenia (SZ) pathophysiology with normalization of aberrant circuit activity proposed as a biomarker for antipsychotic efficacy. Cannabidiol (CBD) shows potential as an adjunctive antipsychotic therapy; however, potential sex effects in these drug interactions remain unknown. In the present study, we sought to elucidate sex effects of CBD coadministration with the atypical antipsychotic iloperidone (ILO) on the activity of primary cortical neuron cultures derived from the rat methylazoxymethanol acetate (MAM) model used for the study of SZ. Spontaneous network activity measurements were obtained using a multielectrode array at baseline and following administration of CBD or ILO alone, or combined. At baseline, MAM male neurons displayed increased bursting activity whereas MAM female neurons exhibited no difference in bursting activity compared to sex-matched controls. CBD administered alone showed a rapid but transient increase in neuronal activity in the MAM networks, an effect more pronounced in females. Furthermore, ILO had an additive effect on CBD-induced elevations in activity in the MAM male neurons. In the MAM female neurons, CBD or ILO administration resulted in time-dependent elevations in neuronal activity, but the short-term CBD-induced increases in activity were lost when CBD and ILO were combined. Our findings indicate that CBD induces rapid increases in cortical neuronal activity, with sex-specific drug interactions upon ILO coadministration. This suggests that sex should be a consideration when implementing adjunct therapy for treatment of SZ.

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Comparison of Acute Effects of Neurotoxic Compounds on Network Activity in Human and Rodent Neural Cultures

Toxicological Sciences ◽

10.1093/toxsci/kfab008 ◽

2021 ◽

Author(s):

L Saavedra ◽

K Wallace ◽

Tf Freudenrich ◽

M Mall ◽

Wr Mundy ◽

...

Keyword(s):

Neural Network ◽

Neuronal Activity ◽

Neuronal Cells ◽

Environmental Chemicals ◽

Network Activity ◽

Inhibitory Neurons ◽

Multielectrode Arrays ◽

Cortical Cultures ◽

Neural Cultures

Abstract Assessment of neuroactive effects of chemicals in cell-based assays remains challenging as complex functional tissue is required for biologically relevant readouts. Recent in vitro models using rodent primary neural cultures grown on multielectrode arrays (MEAs) allow quantitative measurements of neural network activity suitable for neurotoxicity screening. However, robust systems for testing effects on network function in human neural models are still lacking. The increasing number of differentiation protocols for generating neurons from human induced pluripotent stem cells (hiPSCs) holds great potential to overcome the unavailability of human primary tissue and expedite cell-based assays. Yet, the variability in neuronal activity, prolonged ontogeny and rather immature stage of most neuronal cells derived by standard differentiation techniques greatly limit their utility for screening neurotoxic effects on human neural networks. Here, we used excitatory and inhibitory neurons, separately generated by direct reprogramming from hiPSCs, together with primary human astrocytes to establish highly functional cultures with defined cell ratios. Such neuron/glia co-cultures exhibited pronounced neuronal activity and robust formation of synchronized network activity on MEAs, albeit with noticeable delay compared to primary rat cortical cultures. We further investigated acute changes of network activity in human neuron/glia co-cultures and rat primary cortical cultures in response to compounds with known adverse neuroactive effects, including GABAA receptor antagonists and multiple pesticides. Importantly, we observed largely corresponding concentration-dependent effects on multiple neural network activity metrics using both neural culture types. These results demonstrate the utility of directly converted neuronal cells from hiPSCs for functional neurotoxicity screening of environmental chemicals.

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Dynamics of neuronal activity in the cerebral neocortex during human epileptic seizures revealed by microelectrode recordings

10.26226/morressier.5b31ec712afeeb001345ae1e ◽

2018 ◽

Author(s):

Jonas Zimmermann ◽

Pierre Megevand ◽

Aude Yulzari ◽

John Donoghue ◽

Rees Cosgrove ◽

...

Keyword(s):

Neuronal Activity ◽

Epileptic Seizures ◽

Microelectrode Recordings ◽

Cerebral Neocortex

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Dementia with Lewy bodies—associated ß-synuclein mutations V70M and P123H cause mutation-specific neuropathological lesions

Human Molecular Genetics ◽

10.1093/hmg/ddab036 ◽

2021 ◽

Author(s):

Maryna Psol ◽

Sofia Guerin Darvas ◽

Kristian Leite ◽

Sameehan U Mahajani ◽

Mathias Bähr ◽

...

Keyword(s):

Neuronal Network ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Sporadic Case ◽

Network Activity ◽

Proteinase K ◽

Neuronal Network Activity ◽

Distinct Disease

Abstract ß-Synuclein (ß-Syn) has long been considered to be an attenuator for the neuropathological effects caused by the Parkinson’s disease-related α-Synuclein (α-Syn) protein. However, recent studies demonstrated that overabundant ß-Syn can form aggregates and induce neurodegeneration in CNS neurons in vitro and in vivo, albeit at a slower pace as compared to α-Syn. Here we demonstrate that ß-Syn mutants V70M, detected in a sporadic case of Dementia with Lewy Bodies (DLB), and P123H, detected in a familial case of DLB, robustly aggravate the neurotoxic potential of ß-Syn. Intriguingly, the two mutations trigger mutually exclusive pathways. ß-Syn V70M enhances morphological mitochondrial deterioration and degeneration of dopaminergic and non-dopaminergic neurons, but has no influence on neuronal network activity. Conversely, ß-Syn P123H silences neuronal network activity, but does not aggravate neurodegeneration. ß-Syn WT, V70M and P123H formed proteinase K (PK) resistant intracellular fibrils within neurons, albeit with less stable C-termini as compared to α-Syn. Under cell free conditions, ß-Syn V70M demonstrated a much slower pace of fibril formation as compared to WT ß-Syn, and P123H fibrils present with a unique phenotype characterized by large numbers of short, truncated fibrils. Thus, it is possible that V70M and P123H cause structural alterations in ß-Syn, that are linked to their distinct neuropathological profiles. The extent of the lesions caused by these neuropathological profiles is almost identical to that of overabundant α-Syn, and thus likely to be directly involved into etiology of DLB. Over all, this study provides insights into distinct disease mechanisms caused by mutations of ß-Syn.

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Aη-α and Aη-β peptides impair LTP ex vivo within the low nanomolar range and impact neuronal activity in vivo

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00860-1 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Maria Mensch ◽

Jade Dunot ◽

Sandy M. Yishan ◽

Samuel S. Harris ◽

Aline Blistein ◽

...

Keyword(s):

Neuronal Activity ◽

Ex Vivo ◽

Long Term Potentiation ◽

Network Activity ◽

Strongly Correlated ◽

App Processing ◽

Term Potentiation ◽

Hippocampal Network

Abstract Background Amyloid precursor protein (APP) processing is central to Alzheimer’s disease (AD) etiology. As early cognitive alterations in AD are strongly correlated to abnormal information processing due to increasing synaptic impairment, it is crucial to characterize how peptides generated through APP cleavage modulate synapse function. We previously described a novel APP processing pathway producing η-secretase-derived peptides (Aη) and revealed that Aη–α, the longest form of Aη produced by η-secretase and α-secretase cleavage, impaired hippocampal long-term potentiation (LTP) ex vivo and neuronal activity in vivo. Methods With the intention of going beyond this initial observation, we performed a comprehensive analysis to further characterize the effects of both Aη-α and the shorter Aη-β peptide on hippocampus function using ex vivo field electrophysiology, in vivo multiphoton calcium imaging, and in vivo electrophysiology. Results We demonstrate that both synthetic peptides acutely impair LTP at low nanomolar concentrations ex vivo and reveal the N-terminus to be a primary site of activity. We further show that Aη-β, like Aη–α, inhibits neuronal activity in vivo and provide confirmation of LTP impairment by Aη–α in vivo. Conclusions These results provide novel insights into the functional role of the recently discovered η-secretase-derived products and suggest that Aη peptides represent important, pathophysiologically relevant, modulators of hippocampal network activity, with profound implications for APP-targeting therapeutic strategies in AD.

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