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.

Mitochondria in Neuroplasticity, Neurologic Disease and Aging.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-2-SCI-2 ◽  
Author(s):  
Mark P. Mattson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Bone Marrow ◽  
Learning And Memory ◽  
Neuronal Excitability ◽  
Epileptic Seizures ◽  
Receptor Expression ◽  
Health And Disease ◽  
Energy Deprivation ◽  
The Brain

Abstract Abstract SCI-2 Brain cells are influenced in health and disease by several types of bone marrow-derived cells (BMDC) that either reside in, or are recruited to, the brain. Microglia are macrophage-like cells that continuously surveil the brain, and respond to injury, infection or disease by endocytosing damaged/dead cells and microorganisms, and by producing pro-inflammatory cytokines. Lymphocytes of various phenotypes enter the brain in large numbers in response to acute injury (stroke, severe epileptic seizures, trauma) or chronic disease (multiple sclerosis, Alzheimer's disease). While microglia and lymphocytes are best known for their adverse effects on neuronal function and survival in injury or disease (Arumugam et al., Nat Med. 2006; 12:621-3), recent findings suggest that these cells may also serve important beneficial roles in processes such as learning and memory (Ziv et al. Nat Neurosci. 2006; 9:268-75). Here I describe how BMDC can affect neuronal excitability and mitochondrial function in normal physiological settings and in disease states. We have found that low concentrations of tumor necrosis factor (TNF), which is produced by microglia/macrophages and lymphocytes, can promote neuronal survival and synaptic plasticity by activating the transcription factor NF-kB to induce the expression of glutamate receptor subunits, mitochondrial SOD2 and Bcl2 (Mattson and Meffert, Cell Death Differ. 2006; 13:852-60). When bone marrow from TNF receptor-deficient mice was transplanted into irradiated wild type mice, neurons in the brain were more vulnerable to epileptic seizures, suggesting that TNF suppresses neuronal excitability (Guo et al., Neuromolecular Med. 2004; 5:219-34). In other studies we found that a mutation in presenilin-1 (PS1) that causes early-onset inherited Alzheimer's disease (AD) perturbs lymphocyte signaling (Morgan et al., Neuromolecular Med. 2007; 9:35-45). Splenic T cells isolated from PS1 mutant knockin mice respond poorly to proliferative signals and have downregulated cluster designation 3 and interleukin (IL)- 2-receptor expression necessary for a normal T-cell immune response. The adverse effect of mutant PS1 involves perturbed calcium regulation and cytokine signaling in lymphocytes, and associated sensitivity of lymphocytes to mitochondria-mediated apoptosis. These findings suggest that abnormalities in immune function might play roles in the pathogenesis of AD. Finally, I describe very recent findings that suggest roles for toll-like receptor signaling in learning and memory processes, and in neuronal responses to energy deprivation (Tang et al., Proc Natl Acad Sci U S A. 2007; 104:13798-803). Emerging findings therefore suggest that both innate and humoral signaling from BMDC to neurons play interesting roles in regulating neuronal plasticity and energy metabolism in health and disease. Disclosures No relevant conflicts of interest to declare.

scholarly journals Plasticity of GABAA Receptors during Pregnancy and Postpartum Period: From Gene to Function

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Valentina Licheri ◽  
Giuseppe Talani ◽  
Ashish A. Gorule ◽  
Maria Cristina Mostallino ◽  
Giovanni Biggio ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Gabaa Receptors ◽  
Postpartum Period ◽  
Neuronal Excitability ◽  
Receptor Expression ◽  
Neuroactive Steroids ◽  
Receptor Function ◽  
Pregnancy And Postpartum ◽  
Sudden Decrease ◽  
New Treatments

Pregnancy needs complex pathways that together play a role in proper growth and protection of the fetus preventing its premature loss. Changes during pregnancy and postpartum period include the manifold machinery of neuroactive steroids that plays a crucial role in neuronal excitability by local modulation of specific inhibitory receptors: the GABAA receptors. Marked fluctuations in both blood and brain concentration of neuroactive steroids strongly contribute to GABAA receptor function and plasticity. In this review, we listed several interesting results regarding the regulation and plasticity of GABAA receptor function during pregnancy and postpartum period in rats. The increase in brain levels of neuroactive steroids during pregnancy and their sudden decrease immediately before delivery are causally related to changes in the expression/function of specific GABAA receptor subunits in the hippocampus. These data suggest that alterations in GABAA receptor expression and function may be related to neurological and psychiatric disorders associated with crucial periods in women. These findings could help to provide potential new treatments for these women’s disabling syndromes.

scholarly journals Gain-of-function GABRB3 variants identified in vigabatrin-hypersensitive epileptic encephalopathies

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Nathan L Absalom ◽  
Vivian W Y Liao ◽  
Kavitha Kothur ◽  
Dinesh C Indurthi ◽  
Bruce Bennetts ◽  
...  
Keyword(s):  
De Novo ◽  
Drug Effects ◽  
Receptor Expression ◽  
Aminobutyric Acid ◽  
Loss Of Function ◽  
Molecular Phenotype ◽  
Gain Of Function ◽  
Gene Encoding ◽  
Epileptic Encephalopathies ◽  
Receptor Phenotype

Abstract Variants in the GABRB3 gene encoding the β3-subunit of the γ-aminobutyric acid type A ( receptor are associated with various developmental and epileptic encephalopathies. Typically, these variants cause a loss-of-function molecular phenotype whereby γ-aminobutyric acid has reduced inhibitory effectiveness leading to seizures. Drugs that potentiate inhibitory GABAergic activity, such as nitrazepam, phenobarbital or vigabatrin, are expected to compensate for this and thereby reduce seizure frequency. However, vigabatrin, a drug that inhibits γ-aminobutyric acid transaminase to increase tonic γ-aminobutyric acid currents, has mixed success in treating seizures in patients with GABRB3 variants: some patients experience seizure cessation, but there is hypersensitivity in some patients associated with hypotonia, sedation and respiratory suppression. A GABRB3 variant that responds well to vigabatrin involves a truncation variant (p.Arg194*) resulting in a clear loss-of-function. We hypothesized that patients with a hypersensitive response to vigabatrin may exhibit a different γ-aminobutyric acid A receptor phenotype. To test this hypothesis, we evaluated the phenotype of de novo variants in GABRB3 (p.Glu77Lys and p.Thr287Ile) associated with patients who are clinically hypersensitive to vigabatrin. We introduced the GABRB3 p.Glu77Lys and p.Thr287Ile variants into a concatenated synaptic and extrasynaptic γ-aminobutyric acid A receptor construct, to resemble the γ-aminobutyric acid A receptor expression by a patient heterozygous for the GABRB3 variant. The mRNA of these constructs was injected into Xenopus oocytes and activation properties of each receptor measured by two-electrode voltage clamp electrophysiology. Results showed an atypical gain-of-function molecular phenotype in the GABRB3 p.Glu77Lys and p.Thr287Ile variants characterized by increased potency of γ-aminobutyric acid A without change to the estimated maximum open channel probability, deactivation kinetics or absolute currents. Modelling of the activation properties of the receptors indicated that either variant caused increased chloride flux in response to low concentrations of γ-aminobutyric acid that mediate tonic currents. We therefore propose that the hypersensitivity reaction to vigabatrin is a result of GABRB3 variants that exacerbate GABAergic tonic currents and caution is required when prescribing vigabatrin. In contrast, drug strategies increasing tonic currents in loss-of-function variants are likely to be a safe and effective therapy. This study demonstrates that functional genomics can explain beneficial and adverse anti-epileptic drug effects, and propose that vigabatrin should be considered in patients with clear loss-of-function GABRB3 variants.

scholarly journals The Rose Bengal Test in Human Brucellosis: A Neglected Test for the Diagnosis of a Neglected Disease

2011 ◽  
Vol 5 (4) ◽  
pp. e950 ◽  
Author(s):  
Ramón Díaz ◽  
Aurora Casanova ◽  
Javier Ariza ◽  
Ignacio Moriyón
Keyword(s):  
Rose Bengal ◽  
Human Brucellosis ◽  
Neglected Disease ◽  
Rose Bengal Test ◽  
The Rose

Hemoglobin metabolites mimic benzodiazepines and are possible mediators of hepatic encephalopathy

Blood ◽  
2003 ◽  
Vol 102 (4) ◽  
pp. 1525-1528 ◽  
Author(s):  
Brian J. Ruscito ◽  
Neil L. Harrison
Keyword(s):  
Cognitive Impairment ◽  
Hepatic Encephalopathy ◽  
Synaptic Transmission ◽  
Liver Failure ◽  
Gabaa Receptor ◽  
Protoporphyrin Ix ◽  
Aminobutyric Acid ◽  
Endogenous Ligands ◽  
Inhibitory Synaptic Transmission ◽  
Clinical Observations

Abstract Liver failure is often accompanied by cognitive impairment and coma, a syndrome known as hepatic encephalopathy (HE). The administration of flumazenil, a benzodiazepine (BZ) antagonist, is effective in reversing the symptoms of HE in many patients. These clinical observations gave rise to notions of an endogenous BZ-like mechanism in HE, but to date no viable candidate compounds have been characterized. We show here that the hemoglobin (Hb) metabolites hemin and protoporphyrin IX (PPIX) interact with the BZ site on the γ-aminobutyric acid (GABAA) receptor and enhance inhibitory synaptic transmission in a manner similar to diazepam and zolpidem. This finding suggests that hemin and PPIX are neuroactive porphyrins capable of acting as endogenous ligands for the central BZ site. The accumulation of these porphyrins under pathophysiologic conditions provides a potentially novel mechanism for the central manifestations of HE.

scholarly journals 139 Epileptic Seizures and Ability to Work in Cavernous Angioma Located Within Eloquent Brain Areas

Neurosurgery ◽  
2018 ◽  
Vol 65 (CN_suppl_1) ◽  
pp. 93-94
Author(s):  
Marc Zanello ◽  
Megan Still ◽  
John Gooden ◽  
Henry Colle ◽  
Michel Wager ◽  
...  
Keyword(s):  
Epileptic Seizures ◽  
Cavernous Angioma ◽  
Ability To Work ◽  
Brain Areas
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