Histological Characterization of the Irritative Zones in Focal Cortical Dysplasia Using a Preclinical Rat Model

Deshmukh, Abhay; Leichner, Jared; Bae, Jihye; Song, Yinchen; Valdés-Hernández, Pedro A.; Lin, Wei-Chiang; Riera, Jorge J.

doi:10.3389/fncel.2018.00052

Cited by 6 publications

(4 citation statements)

References 52 publications

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“…Activation of NMDAR allows the influx of sodium ions and the outflow of potassium ions, which ensures depolarization of the neuronal membrane. It has been shown that in foci of focal cortical dysplasia characterized by high epileptogenicity, NMDAR expression increases [60]. In addition, pathological activation of NMDAR leads to hyperexcitation and increased activity of neurons, which is the pathophysiological basis for epileptogenesis [61,62].…”

Section: Discussionmentioning

confidence: 99%

Socrates: A Novel N-Ethyl-N-nitrosourea-Induced Mouse Mutant with Audiogenic Epilepsy

Varlamova,

Borisova,

Evstratova

et al. 2023

IJMS

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Epilepsy is one of the common neurological diseases that affects not only adults but also infants and children. Because epilepsy has been studied for a long time, there are several pharmacologically effective anticonvulsants, which, however, are not suitable as therapy for all patients. The genesis of epilepsy has been extensively investigated in terms of its occurrence after injury and as a concomitant disease with various brain diseases, such as tumors, ischemic events, etc. However, in the last decades, there are multiple reports that both genetic and epigenetic factors play an important role in epileptogenesis. Therefore, there is a need for further identification of genes and loci that can be associated with higher susceptibility to epileptic seizures. Use of mouse knockout models of epileptogenesis is very informative, but it has its limitations. One of them is due to the fact that complete deletion of a gene is not, in many cases, similar to human epilepsy-associated syndromes. Another approach to generating mouse models of epilepsy is N-Ethyl-N-nitrosourea (ENU)-directed mutagenesis. Recently, using this approach, we generated a novel mouse strain, soc (socrates, formerly s8-3), with epileptiform activity. Using molecular biology methods, calcium neuroimaging, and immunocytochemistry, we were able to characterize the strain. Neurons isolated from soc mutant brains retain the ability to differentiate in vitro and form a network. However, soc mutant neurons are characterized by increased spontaneous excitation activity. They also demonstrate a high degree of Ca2+ activity compared to WT neurons. Additionally, they show increased expression of NMDA receptors, decreased expression of the Ca2+-conducting GluA2 subunit of AMPA receptors, suppressed expression of phosphoinositol 3-kinase, and BK channels of the cytoplasmic membrane involved in protection against epileptogenesis. During embryonic and postnatal development, the expression of several genes encoding ion channels is downregulated in vivo, as well. Our data indicate that soc mutation causes a disruption of the excitation–inhibition balance in the brain, and it can serve as a mouse model of epilepsy.

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Section: Discussionmentioning

confidence: 99%

Socrates: A Novel N-Ethyl-N-nitrosourea-Induced Mouse Mutant with Audiogenic Epilepsy

Varlamova,

Borisova,

Evstratova

et al. 2023

IJMS

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“…The pilocarpine model was used to induce temporal lobe epilepsy in rats of approximately 4 weeks of age, using a procedure similar to that carried out previously in ref and . Upon reaching a state of spontaneously recurring seizures, one of the subject rats was used for the in vivo experiments.…”

Section: Methodsmentioning

confidence: 99%

Fully Passive Flexible Wireless Neural Recorder for the Acquisition of Neuropotentials from a Rat Model

et al. 2019

Self Cite

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Wireless implantable neural interfaces can record high-resolution neuropotentials without constraining patient movement. Existing wireless systems often require intracranial wires to connect implanted electrodes to an external head stage or/and deploy an application-specific integrated circuit (ASIC), which is battery-powered or externally power-transferred, raising safety concerns such as infection, electronics failure, or heat-induced tissue damage. This work presents a biocompatible, flexible, implantable neural recorder capable of wireless acquisition of neuropotentials without wires, batteries, energy harvesting units, or active electronics. The recorder, fabricated on a thin polyimide substrate, features a small footprint of 9 mm × 8 mm × 0.3 mm and is composed of passive electronic components. The absence of active electronics on the device leads to near zero power consumption, inherently avoiding the catastrophic failure of active electronics. We performed both in vitro validation in a tissue-simulating phantom and in vivo validation in an epileptic rat. The fully passive wireless recorder was implanted under rat scalp to measure neuropotentials from its contact electrodes. The implanted wireless recorder demonstrated its capability to capture low voltage neuropotentials, including somatosensory evoked potentials (SSEPs), and interictal epileptiform discharges (IEDs). Wirelessly recorded SSEP and IED signals were directly compared to those from wired electrodes to demonstrate the efficacy of the wireless data. In addition, a convoluted neural network-based machine learning algorithm successfully achieved IED signal recognition accuracy as high as 100 and 91% in wired and wireless IED data, respectively. These results strongly support the fully passive wireless neural recorder's capability to measure neuropotentials as low as tens of microvolts. With further improvement, the recorder system presented in this work may find wide applications in future brain machine interface systems.

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“…In human resected tissues, the N1R immunoreactivity of dysplastic and dysmorphic neurons was increased; moreover, NR2A and NR2B were also overexpressed, which is a feature of hyperexcitable developing neurons [21,23]. In CD animal models, NR2B and NR1 were also upregulated in lesions [17,24]. Furthermore, in vitro ifenprodil reduced the excitability of CD brain tissue slices, and in vivo administration of ifenprodil blocked NR2B; these results clari ed the important roles of NR2B and NR1 upregulation in increasing epileptogenicity in the rat frozen model of CD [25,26].…”

Section: Abnormal Excitation In CDmentioning

confidence: 99%

“…The intensity and frequency distribution of EEG was obtained from the power spectrum by fast Fourier transform with a 2-s Hanning window across a continuous 1-500 Hz frequency range. The absolute power (μV2) of each EEG frequency band [delta (1)(2)(3)(4) Hz), theta (4-8 Hz), alpha (8-13 Hz), beta (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), lower gamma (30-60 Hz), higher gamma (60-80 Hz), ripple (80-250 Hz) and fast ripple (250-500 Hz)] at selected pre-pilocarpine resting periods (background activity) and post-pilocarpine ictal periods were compared between the rHMGB1-treatment rats and the control rats. Time-frequency and wavelet analyses were performed using Morlet wavelets in Brainstorm, which was developed with MATLAB software.…”

Section: Eeg Acquisition and Analysismentioning

confidence: 99%

Abnormal Rat Cortical Development Induced by Ventricular Injection of rHMGB1 Mimicked the Pathophysiology of Human Cortical Dysplasia

Yang

Zhang

Wang

et al. 2020

Preprint

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Background Cortical dysplasia (CD) is a common cause of drug-resistant epilepsy. Increasingly, innate immunity is involved in CD with epilepsy. However, it is unclear whether innate immune factors contribute to induce epileptogenic CD. Here, we injected recombinant human HMGB1 (rHMGB1) into the embryonic rat ventricle to determine whether rHMGB1 can induce epileptogenic CD with pathophysiological characteristics similar to those of human CD.Methods At gestational day 14.5, rHMGB1 was injected into the ventricles of Sprague Dawley (SD) rat embryos. At 2 months postnatal, the effects of rHMGB1 on cortex construction were examined by Nissl staining; the alterations of nerve tissue were detected using immunostaining. At 3 months postnatal, the susceptibility and severity of pilocarpine-induced seizures and the spontaneous epileptic discharges were evaluated by EEG. Open-field tests, novel object recognition tests, and Morris water maze tests were performed to observe the behavior of rHMGB1-treated rats.Results The results showed cortical organization was severely disrupted in the rHMGB1-treated rats, and microgyria and heterotopia also emerged; additionally, disoriented neurons, dysmorphic neurons, and dysplastic neurons were found in the cortical lesions and heterotopias. Subcortical heterotopia also appeared in the white matter and the gray-white junction of the rHMGB1-treated rats. Moreover, the numbers of neurons and astrocytes were increased in the cortical lesions; the neuronal dendrites were thickened, randomly oriented, and frequently crossed each other. Moreover, the immunoreactivity of NR2A, NR2B, NR1, GAD65/67, EAAT1 and EAAT2 indicated that the excitation of cortical lesions and heterotopia were significantly increased. Furthermore, EEG showed more susceptibility and severity of seizures in rHMGB1-treatment rats compared with the control rats. Intriguingly, spontaneous nonepileptic seizure discharges were also detected in the rHMGB1-treated rats after 5 months of age, and spike-wave discharges of approximately 8 Hz were the most significantly increased synchronously propagated waves throughout the general brain cortex.Conclusions These results indicated that rHMGB1 exposure during pregnancy can modify the cerebral structure of offspring, which results in increased susceptibility to seizures and mimics the pathophysiological characteristics of human CD. Those results suggested that HMGB1 upregulation resulting from various insults could contribute to the development of epileptogenic CD during pregnancy.

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Histological Characterization of the Irritative Zones in Focal Cortical Dysplasia Using a Preclinical Rat Model

Cited by 6 publications

References 52 publications

Socrates: A Novel N-Ethyl-N-nitrosourea-Induced Mouse Mutant with Audiogenic Epilepsy

Socrates: A Novel N-Ethyl-N-nitrosourea-Induced Mouse Mutant with Audiogenic Epilepsy

Fully Passive Flexible Wireless Neural Recorder for the Acquisition of Neuropotentials from a Rat Model

Abnormal Rat Cortical Development Induced by Ventricular Injection of rHMGB1 Mimicked the Pathophysiology of Human Cortical Dysplasia

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