Microglia depletion exacerbates acute seizures and hippocampal neuronal degeneration in mouse models of epilepsy

2020 ◽  
Vol 319 (3) ◽  
pp. C605-C610
Author(s):  
Mei Liu ◽  
Lijuan Jiang ◽  
Min Wen ◽  
Yue Ke ◽  
Xiangzhen Tong ◽  
...  
Keyword(s):  
Mouse Models ◽  
Neuronal Excitability ◽  
Neuronal Degeneration ◽  
Epileptic Seizures ◽  
Gabaergic Neurons ◽  
Seizure Severity ◽  
Neuronal Excitation ◽  
Acute Seizures ◽  
Models Of Epilepsy

Epileptic seizures are the manifestation of hypersynchronous and excessive neuronal excitation. While the glutamatergic and GABAergic neurons play major roles in shaping fast neuronal excitation/inhibition homeostasis, it is well illustrated that astrocytes profoundly regulate neuronal excitation by controlling glutamate, GABA, cannabinoids, adenosine, and concentration of K+ around neurons. However, little is known about whether microglia take part in the regulation of acute neuronal excitation and ongoing epileptic behaviors. We proposed that if microglia are innately ready to respond to epileptic overexcitation, depletion of microglia might alter neuronal excitability and severity of acute epileptic seizures. We found that microglia depletion by plx3397, an inhibitor of CSF1R, exacerbates seizure severity and excitotoxicity-induced neuronal degeneration, indicating that microglia are rapidly responsive to the change of excitation/inhibition homeostasis and participate in the protection of neurons from overexcitation.

scholarly journals Altered A-type potassium channel function in the nucleus tractus solitarii in acquired temporal lobe epilepsy

2019 ◽  
Vol 121 (1) ◽  
pp. 177-187 ◽  
Author(s):  
Isabel D. Derera ◽  
Katalin Cs. Smith ◽  
Bret N. Smith
Keyword(s):  
Temporal Lobe Epilepsy ◽  
Mouse Models ◽  
Temporal Lobe ◽  
Neuronal Excitability ◽  
Gabaergic Neurons ◽  
Nucleus Tractus Solitarii ◽  
Sudden Unexpected Death ◽  
Inactivation Kinetics ◽  
Unexpected Death ◽  
Increased Risk

Sudden unexpected death in epilepsy (SUDEP) is among the leading causes of death in people with epilepsy. Individuals with temporal lobe epilepsy (TLE) have a high risk for SUDEP because the seizures are often medically intractable. Neurons in the nucleus tractus solitarii (NTS) have been implicated in mouse models of SUDEP and play a critical role in modulating cardiorespiratory and autonomic output. Increased neuronal excitability of inhibitory, GABAergic neurons in the NTS develops during epileptogenesis, and NTS dysfunction has been implicated in mouse models of SUDEP. In this study we used the pilocarpine-induced status epilepticus model of TLE (i.e., pilo-SE mice) to investigate the A-type voltage-gated K+ channel as a potential contributor to increased excitability in GABAergic NTS neurons during epileptogenesis. Compared with age-matched control mice, pilo-SE mice displayed an increase in spontaneous action potential frequency and half-width 9–12 wk after treatment. Activity of GABAergic NTS neurons from pilo-SE mice showed less sensitivity to 4-aminopyridine. Correspondingly, reduced A-type K+ current amplitude was detected in these neurons, with no change in activation or inactivation kinetics. No changes were observed in Kv4.1, Kv4.2, Kv4.3, KChIP1, KChIP3, or KChIP4 mRNA expression. These changes contribute to the increased excitability in GABAergic NTS neurons that develops in TLE and may provide insight into potential mechanisms contributing to the increased risk for cardiorespiratory collapse and SUDEP in this model. NEW & NOTEWORTHY Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death in epilepsy, and dysfunction in central autonomic neurons may play a role. In a mouse model of acquired epilepsy, GABAergic neurons in the nucleus tractus solitarii developed a reduced amplitude of the A-type current, which contributes to the increased excitability seen in these neurons during epileptogenesis. Neuronal excitability changes in inhibitory central vagal circuitry may increase the risk for cardiorespiratory collapse and SUDEP.

scholarly journals LSD1 Neurospecific Alternative Splicing Controls Neuronal Excitability in Mouse Models of Epilepsy

2014 ◽  
Vol 25 (9) ◽  
pp. 2729-2740 ◽  
Author(s):  
Francesco Rusconi ◽  
Leda Paganini ◽  
Daniela Braida ◽  
Luisa Ponzoni ◽  
Emanuela Toffolo ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Mouse Models ◽  
Neuronal Excitability ◽  
Models Of Epilepsy

scholarly journals Home-cage Monitoring Ascertains Signatures of Ictal and Interictal Behavior In Mouse Models of Generalized Seizures

2019 ◽  
Author(s):  
Miranda J. Jankovic ◽  
Paarth P. Kapadia ◽  
Vaishnav Krishnan
Keyword(s):  
Mouse Models ◽  
Home Cage ◽  
Psychiatric Symptoms ◽  
Epileptic Seizures ◽  
Emotional Behavior ◽  
Dravet Syndrome ◽  
Brain Disorder ◽  
Seizure Severity ◽  
Increased Risk ◽  
Epilepsy Models

AbstractEpilepsy is a significant contributor to worldwide disability. In epilepsy, disability has two components: ictal (pertaining to the burden of unpredictable seizures and associated medical complications including death) and interictal (pertaining to more pervasive debilitating changes in cognitive and emotional behavior). In this study, we objectively and noninvasively appraise correlates of ictal and interictal disability in mice using instrumented home-cage chambers designed to assay kinematic and appetitive behavioral measures. We discover that in C57BL/6J mice, intraperitoneal injections of the chemoconvulsant pentylenetetrazole (PTZ) acutely result in complex and dynamic changes in movement and sheltering behavior that evolve (or kindle) with repeated daily injections, and which are separate from the occurrence of convulsions. By closely studying “interictal” periods (between PTZ injections), we identify a syndrome of nocturnal hypoactivity and increased sheltering behavior. We observe elements of this interictal behavioral syndrome in seizure-prone DBA/2J mice and in mice with a pathogenic Scn1a mutation (modeling Dravet syndrome). Through analyzing their responses to PTZ, we illustrate how convulsive severity and “behavioral” severity are distinct and independent aspects of overall seizure severity. Our results illustrate the utility of an ethologically centered automated approach to quantitatively appraise murine expressions of disability in mouse models of seizures and epilepsy. In doing so, this study highlights the very unique psychopharmacological profile of PTZ.Significance StatementEpilepsy is a brain disorder characterized by a pervasively increased risk to develop epileptic seizures. Sadly, patients with epilepsy also experience high rates of anxiety, depression and other psychiatric symptoms that significantly increase overall disability. While many mouse models of seizures and epilepsy exist, we need improved techniques to measure how new treatments impact not only seizure occurrence, but also emotional changes that persist in between seizures. In this study, we apply the technique of home-cage monitoring to clarify precisely how spontaneous mouse behavior is altered in three distinct epilepsy models. Our work illustrates the importance of an ethologically centered appreciation of neuropsychiatric disability in mice and clarifies a new approach to the measurement of “seizure severity”.

scholarly journals Multimodal in vivo recording using transparent graphene microelectrodes illuminates spatiotemporal seizure dynamics at the microscale

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Nicolette Driscoll ◽  
Richard E. Rosch ◽  
Brendan B. Murphy ◽  
Arian Ashourvan ◽  
Ramya Vishnubhotla ◽  
...  
Keyword(s):  
Temporal Resolution ◽  
Spatial Scales ◽  
Epileptic Seizures ◽  
Therapeutic Interventions ◽  
State Transitions ◽  
Integrated Analysis ◽  
High Temporal Resolution ◽  
Seizure Onset ◽  
Acute Seizures

AbstractNeurological disorders such as epilepsy arise from disrupted brain networks. Our capacity to treat these disorders is limited by our inability to map these networks at sufficient temporal and spatial scales to target interventions. Current best techniques either sample broad areas at low temporal resolution (e.g. calcium imaging) or record from discrete regions at high temporal resolution (e.g. electrophysiology). This limitation hampers our ability to understand and intervene in aberrations of network dynamics. Here we present a technique to map the onset and spatiotemporal spread of acute epileptic seizures in vivo by simultaneously recording high bandwidth microelectrocorticography and calcium fluorescence using transparent graphene microelectrode arrays. We integrate dynamic data features from both modalities using non-negative matrix factorization to identify sequential spatiotemporal patterns of seizure onset and evolution, revealing how the temporal progression of ictal electrophysiology is linked to the spatial evolution of the recruited seizure core. This integrated analysis of multimodal data reveals otherwise hidden state transitions in the spatial and temporal progression of acute seizures. The techniques demonstrated here may enable future targeted therapeutic interventions and novel spatially embedded models of local circuit dynamics during seizure onset and evolution.

scholarly journals Leukocyte–Endothelial Adhesion Mechanisms in Epilepsy: Cheers and Jeers

2009 ◽  
Vol 9 (4) ◽  
pp. 118-121 ◽  
Author(s):  
Annamaria Vezzani ◽  
Damir Janigro
Keyword(s):  
Neuronal Excitability ◽  
World Population ◽  
Brain Vessels ◽  
Acute Seizures ◽  
Leukocyte Integrins ◽  
Acute Seizure ◽  
Elevated Expression ◽  
Vascular Adhesion ◽  
Spontaneous Recurrent Seizures ◽  
Blocking Antibodies

A Role for Leukocyte-Endothelial Adhesion Mechanisms in Epilepsy. Fabene PF, Navarro MG, Martinello M, Rossi B, Merigo F, Ottoboni L, Bach S, Angiari S, Benati D, Chakir A, Zanetti L, Schio F, Osculati A, Marzola P, Nicolato E, Homeister JW, Xia L, Lowe JB, McEver RP, Osculati F, Sbarbati A, Butcher EC, Constantin G. Nat Med 2008;14(12):1377–1383. The mechanisms involved in the pathogenesis of epilepsy, a chronic neurological disorder that affects approximately one percent of the world population, are not well understood1,2,3. Using a mouse model of epilepsy, we show that seizures induce elevated expression of vascular cell adhesion molecules and enhanced leukocyte rolling and arrest in brain vessels mediated by the leukocyte mucin P-selectin glycoprotein ligand-1 (PSGL-1, encoded by Selplg) and leukocyte integrins41 and L2. Inhibition of leukocyte-vascular interactions, either with blocking antibodies or by genetically interfering with PSGL-1 function in mice, markedly reduced seizures. Treatment with blocking antibodies after acute seizures prevented the development of epilepsy. Neutrophil depletion also inhibited acute seizure induction and chronic spontaneous recurrent seizures. Blood-brain barrier (BBB) leakage, which is known to enhance neuronal excitability, was induced by acute seizure activity but was prevented by blockade of leukocyte-vascular adhesion, suggesting a pathogenetic link between leukocyte-vascular interactions, BBB damage and seizure generation. Consistent with the potential leukocyte involvement in epilepsy in humans, leukocytes were more abundant in brains of individuals with epilepsy than in controls. Our results suggest leukocyte-endothelial interaction as a potential target for the prevention and treatment of epilepsy.

scholarly journals Evaluation of Serum Calcium Levels in Patients with Epileptic Seizure

2020 ◽  
Vol 5 (2) ◽  
pp. 35-37
Author(s):  
Bushra Fiza ◽  
Maheep Sinha ◽  
Shalu Sharma ◽  
Sumit Kumar Tiwari
Keyword(s):  
Bone Metabolism ◽  
Serum Calcium ◽  
Epileptic Seizure ◽  
Neuronal Excitability ◽  
Epileptic Seizures ◽  
Bone Metabolism Markers ◽  
Mahatma Gandhi ◽  
Medical College ◽  
The Central Nervous System ◽  
Gandhi Medical College

ABSTRACT Introduction Epilepsy is a disorder of the central nervous system, characterized by an epileptic seizure. Epileptic seizures occur due to abnormal synchronous activity in the brain. Calcium is an essential component of bone. Hypocalcemia enhances neuronal excitability, and there are many causes of which include hypocalcemia, vitamin D deficiency, and PTH resistance. Materials and methods The study was conducted in Department of Biochemistry in association with the Department of Neurology of Mahatma Gandhi Medical College and Hospital, Jaipur. Fifty patients diagnosed for epileptic seizure and 50 controls, visiting the inpatient department (IPD) and outpatient department (OPD) of Neurology fulfilling the inclusion criteria, were enrolled for the study. Result The present study showed significantly lower level of serum calcium in patients with epileptic seizure when compared to controls. Conclusion The serum calcium was measured between epileptic seizure and controls. Our present study showed significantly lower value of calcium. It is therefore suggested that there should be regular screening for calcium in patients with epileptic seizure. The serum calcium is biomarker of bone metabolism; so, the correlation can be further studied with some more bone metabolism markers in epileptic seizure patients. How to cite this article Sharma S, Fiza B, Tiwari SK, et al. Evaluation of Serum Calcium Levels in Patients with Epileptic Seizure. J Mahatma Gandhi Univ Med Sci Tech 2020;5(2):35–37.

scholarly journals Metabotropic glutamate receptor 5 regulates excitability and Kv4.2-containing K+ channels primarily in excitatory neurons of the spinal dorsal horn

2011 ◽  
Vol 105 (6) ◽  
pp. 3010-3021 ◽  
Author(s):  
Hui-Juan Hu ◽  
Robert W. Gereau
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Neuronal Excitability ◽  
Gabaergic Neurons ◽  
Erk Signaling ◽  
Metabotropic Glutamate ◽  
Dorsal Horn Neurons ◽  
Spinal Dorsal ◽  
Excitatory Neurons

Metabotropic glutamate (mGlu) receptors play important roles in the modulation of nociception. Previous studies demonstrated that mGlu5 modulates nociceptive plasticity via activation of ERK signaling. We have reported recently that the Kv4.2 K+ channel subunit underlies A-type currents in spinal cord dorsal horn neurons and that this channel is modulated by mGlu5-ERK signaling. In the present study, we tested the hypothesis that modulation of Kv4.2 by mGlu5 occurs in excitatory spinal dorsal horn neurons. With the use of a transgenic mouse strain expressing enhanced green fluorescent protein (GFP) under control of the promoter for the γ-amino butyric acid (GABA)-synthesizing enzyme, glutamic acid decarboxylase 67 (GAD67), we found that these GABAergic neurons express less Kv4.2-mediated A-type current than non-GAD67-GFP neurons. Furthermore, the mGlu1/5 agonist, (R,S)-3,5-dihydroxyphenylglycine, had no modulatory effects on A-type currents or neuronal excitability in this subgroup of GABAergic neurons but robustly modulated A-type currents and neuronal excitability in non-GFP-expressing neurons. Immunofluorescence studies revealed that Kv4.2 was highly colocalized with markers of excitatory neurons, such as vesicular glutamate transporter 1/2, PKCγ, and neurokinin 1, in cultured dorsal horn neurons. These results indicate that mGlu5-Kv4.2 signaling is associated with excitatory dorsal horn neurons and suggest that the pronociceptive effects of mGlu5 activation in the spinal cord likely involve enhanced excitability of excitatory neurons.

scholarly journals Astrocyte and Neuronal Pannexin1 Contribute Distinctly to Seizures

ASN NEURO ◽  
2019 ◽  
Vol 11 ◽  
pp. 175909141983350 ◽  
Author(s):  
Eliana Scemes ◽  
Libor Velíšek ◽  
Jana Velíšková
Keyword(s):  
Atp Release ◽  
Epileptic Seizures ◽  
Immunohistochemical Analysis ◽  
Adenosine Kinase ◽  
Seizure Outcome ◽  
Release Channel ◽  
Extracellular Adenosine ◽  
Targeted Deletion ◽  
Acute Seizures ◽  
Opposing Effects

ATP- and adenosine-mediated signaling are prominent types of glia–glia and glia–neuron interaction, with an imbalance of ATP/adenosine ratio leading to altered states of excitability, as seen in epileptic seizures. Pannexin1 (Panx1), a member of the gap junction family, is an ATP release channel that is expressed in astrocytes and neurons. Previous studies provided evidence supporting a role for purinergic-mediated signaling via Panx1 channels in seizures; using mice with global deletion of Panx1, it was shown that these channels contribute in maintenance of seizures by releasing ATP. However, nothing is known about the extent to which astrocyte and neuronal Panx1 might differently contribute to seizures. We here show that targeted deletion of Panx1 in astrocytes or neurons has opposing effects on acute seizures induced by kainic acid. The absence of Panx1 in astrocytes potentiates while the absence of Panx1 in neurons attenuates seizure manifestation. Immunohistochemical analysis performed in brains of these mice, revealed that adenosine kinase (ADK), an enzyme that regulates extracellular levels of adenosine, was increased only in seized GFAP-Cre:Panx1f/f mice. Pretreating mice with the ADK inhibitor, idotubercidin, improved seizure outcome and prevented the increase in ADK immunoreactivity. Together, these data suggest that the worsening of seizures seen in mice lacking astrocyte Panx1 is likely related to low levels of extracellular adenosine due to the increased ADK levels in astrocytes. Our study not only reveals an unexpected link between Panx1 channels and ADK but also highlights the important role played by astrocyte Panx1 channels in controlling neuronal activity.

scholarly journals Reactive Glia Inflammatory Signaling Pathways and Epilepsy

2020 ◽  
Vol 21 (11) ◽  
pp. 4096 ◽  
Author(s):  
Pascual Sanz ◽  
Maria Adelaida Garcia-Gimeno
Keyword(s):  
Signaling Pathways ◽  
Inflammatory Mediators ◽  
Feedback Loop ◽  
Common Factor ◽  
Epileptic Seizures ◽  
Brain Inflammation ◽  
Inflammatory Signaling ◽  
Positive Feedback Loop ◽  
Acute Seizures ◽  
Pro Inflammatory Cytokines

Neuroinflammation and epilepsy are interconnected. Brain inflammation promotes neuronal hyper-excitability and seizures, and dysregulation in the glia immune-inflammatory function is a common factor that predisposes or contributes to the generation of seizures. At the same time, acute seizures upregulate the production of pro-inflammatory cytokines in microglia and astrocytes, triggering a downstream cascade of inflammatory mediators. Therefore, epileptic seizures and inflammatory mediators form a vicious positive feedback loop, reinforcing each other. In this work, we have reviewed the main glial signaling pathways involved in neuroinflammation, how they are affected in epileptic conditions, and the therapeutic opportunities they offer to prevent these disorders.

scholarly journals Neuronal Hyperexcitability and Reduction of GABAA-Receptor Expression in the Surround of Cerebral Photothrombosis

1996 ◽  
Vol 16 (5) ◽  
pp. 906-914 ◽  
Author(s):  
Klaus Schiene ◽  
Claus Bruehl ◽  
Karl Zilles ◽  
Meishu Qu ◽  
Georg Hagemann ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Rose Bengal ◽  
Sensorimotor Cortex ◽  
Neuronal Excitability ◽  
Epileptic Seizures ◽  
Receptor Expression ◽  
Aminobutyric Acid ◽  
Brain Areas ◽  
Series Of Experiments ◽  
The Rose

Changes of neuronal excitability and γ-aminobutyric acid (GABAA)-receptor expression were studied in the surround of photothrombotic infarcts, which were produced in the sensorimotor cortex of the rat by using the rose bengal technique. In a first series of experiments, multiunit recordings were performed on anesthetized animals 2–3 mm lateral from the lesion. Mean discharge frequency was considerably higher in recordings from lesioned animals (>100 Hz in the first postlesional week) compared with control animals (mean, 15 Hz). These alterations were already present after 1 day but were most pronounced 3 to 7 days after lesion induction. Thereafter the hyperexcitability declined again, although it remained visible up to 4 months. In a second series of experiments, the GABAA-receptor expression was studied autoradiographically. This revealed a reduction of GABAA receptors in widespread brain areas ipsilateral to the lesion. The reduction was most pronounced in the first days after lesion induction and declined with longer intervals. It is concluded that cortical infarction due to photothrombosis leads to a long-lasting and widespread reduction of GABAA-receptor expression in the surround of the lesion, which is associated with an increased neuronal excitability. Such alterations may be responsible for epileptic seizures that can be observed in some patients after stroke and may contribute to neurologic deficits after stroke.

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