scholarly journals Epileptic Mechanisms Shared by Alzheimer’s Disease: Viewed via the Unique Lens of Genetic Epilepsy

2021 ◽  
Vol 22 (13) ◽  
pp. 7133
Author(s):  
Jing-Qiong Kang
Keyword(s):  
Neurodegenerative Diseases ◽  
Er Stress ◽  
Mouse Models ◽  
Gabaa Receptors ◽  
Early Phase ◽  
Epileptiform Activity ◽  
Complex Interplay ◽  
Gaba Transporter ◽  
Genetic Epilepsy ◽  
Gaba Transporter 1

Our recent work on genetic epilepsy (GE) has identified common mechanisms between GE and neurodegenerative diseases including Alzheimer’s disease (AD). Although both disorders are seemingly unrelated and occur at opposite ends of the age spectrum, it is likely there are shared mechanisms and studies on GE could provide unique insights into AD pathogenesis. Neurodegenerative diseases are typically late-onset disorders, but the underlying pathology may have already occurred long before the clinical symptoms emerge. Pathophysiology in the early phase of these diseases is understudied but critical for developing mechanism-based treatment. In AD, increased seizure susceptibility and silent epileptiform activity due to disrupted excitatory/inhibitory (E/I) balance has been identified much earlier than cognition deficit. Increased epileptiform activity is likely a main pathology in the early phase that directly contributes to impaired cognition. It is an enormous challenge to model the early phase of pathology with conventional AD mouse models due to the chronic disease course, let alone the complex interplay between subclinical nonconvulsive epileptiform activity, AD pathology, and cognition deficit. We have extensively studied GE, especially with gene mutations that affect the GABA pathway such as mutations in GABAA receptors and GABA transporter 1. We believe that some mouse models developed for studying GE and insights gained from GE could provide unique opportunity to understand AD. These include the pathology in early phase of AD, endoplasmic reticulum (ER) stress, and E/I imbalance as well as the contribution to cognitive deficit. In this review, we will focus on the overlapping mechanisms between GE and AD, the insights from mutations affecting GABAA receptors, and GABA transporter 1. We will detail mechanisms of E/I imbalance and the toxic epileptiform generation in AD, and the complex interplay between ER stress, impaired membrane protein trafficking, and synaptic physiology in both GE and AD.

scholarly journals Dibenzoylthiamine Has Powerful Antioxidant and Anti-Inflammatory Properties in Cultured Cells and in Mouse Models of Stress and Neurodegeneration

Biomedicines ◽  
2020 ◽  
Vol 8 (9) ◽  
pp. 361
Author(s):  
Margaux Sambon ◽  
Anna Gorlova ◽  
Alice Demelenne ◽  
Judit Alhama-Riba ◽  
Bernard Coumans ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Diseases ◽  
Cell Line ◽  
Mouse Models ◽  
Cultured Cells ◽  
Therapeutic Potential ◽  
Motor Dysfunction ◽  
Oxidative Stress Marker ◽  
Bv2 Cells ◽  
Anti Inflammatory

Thiamine precursors, the most studied being benfotiamine (BFT), have protective effects in mouse models of neurodegenerative diseases. BFT decreased oxidative stress and inflammation, two major characteristics of neurodegenerative diseases, in a neuroblastoma cell line (Neuro2a) and an immortalized brain microglial cell line (BV2). Here, we tested the potential antioxidant and anti-inflammatory effects of the hitherto unexplored derivative O,S-dibenzoylthiamine (DBT) in these two cell lines. We show that DBT protects Neuro2a cells against paraquat (PQ) toxicity by counteracting oxidative stress at low concentrations and increases the synthesis of reduced glutathione and NADPH in a Nrf2-independent manner. In BV2 cells activated by lipopolysaccharides (LPS), DBT significantly decreased inflammation by suppressing translocation of NF-κB to the nucleus. Our results also demonstrate the superiority of DBT over thiamine and other thiamine precursors, including BFT, in all of the in vitro models. Finally, we show that the chronic administration of DBT arrested motor dysfunction in FUS transgenic mice, a model of amyotrophic lateral sclerosis, and it reduced depressive-like behavior in a mouse model of ultrasound-induced stress in which it normalized oxidative stress marker levels in the brain. Together, our data suggest that DBT may have therapeutic potential for brain pathology associated with oxidative stress and inflammation by novel, coenzyme-independent mechanisms.

DISTRIBUTION OF GABA TRANSPORTER (GAT1) LEVELS IN THE BÖTZINGER COMPLEX AT THE EARLY STAGES OF POSTNATAL DEVELOPMENT IN RATS WITH PRENATAL SEROTONIN DEFICIENCY

2020 ◽  
pp. 7-12
Author(s):  
Л. И. Хожай
Keyword(s):  
Postnatal Development ◽  
Tryptophan Hydroxylase ◽  
Polyclonal Antibodies ◽  
Gaba Transporter ◽  
Early Stages ◽  
Bötzinger Complex ◽  
Neuronal Processes ◽  
Serotonin Deficiency ◽  
Gaba Transporter 1 ◽  
Primary Rabbit

Цель работы - исследование распределения уровня GAT-транспортера ГАМК в комплексе Бетцингера на разных сроках раннего постнатального развития крыс в норме и при пренатальном дефиците серотонина. Материал и методы. Работа проведена на лабораторных крысах линии Wistar. Снижение уровня эндогенного серотонина в эмбриональный период осуществляли методом ингибирования триптофан-гидроксилазы пара-хлорфенилаланином (пХФА). Выявление транспортного белка GAТпроводили посредством иммуногистохимической реакции с использованием первичных кроличьих поликлональных антител anti-GABA transporter1 (AbCam, Великобритания). Мозг исследовали на 5-, 10-е и 20-е сутки постнатального развития. Результаты. В комплексе Бетцингера на ранних сроках постнатального развития у контрольных животных отмечено колебание уровня GAT-транспортера ГАМК. На 1-й неделе жизни уровень GATбыл высоким как в сети отростков и терминалей, так и в синапсах. В течение 2-й недели жизни уровень GATснижался, а к концу 3-й недели - повышался вновь, достигая исходного уровня. Дефицит серотонина в пренатальный период вызывал у подопытных животных существенное увеличение уровня GATв нейропиле комплекса Бетцингера на всех изученных сроках постнатального развития. Выводы. Пренатальный дефицит серотонина приводит к существенному повышению уровня GAT-транспортера ГАМК в ранние сроки постнатального развития, что может приводить к изменению трансмиссии ГАМК и, как следствие, к нарушению баланса тормозных и возбуждающих эффектов в дыхательном ядре. Objective - to study the distribution of GABA transporter 1 (GAT) levels in the Bötzinger complex at the early stages of postnatal development in rats with prenatal serotonin deficiency. Materials and methods. The work was carried out on Wistar line laboratory rats. To reduce the level of endogenous serotonin in the embryonic period, the method of tryptophan hydroxylase inhibition by para-chlorophenylalanine (PCPA) (Sigma, USA) was used. The GAT1 transport protein was detected by immunohistochemical reaction with anti-GABA transporter1 primary rabbit polyclonal antibodies (AbCam, UK). The brain was examined on the 5, 10 and 20 day of postnatal development. Results. At the early stages of postnatal development, a fluctuation in the GAT1 level of the GABA transporter was noted in the Bötzinger complex of control animals. In the first postnatal week, the GAT level was high both in the network of neuronal processes and terminals, and in synapses. During the 2 week of life, the GAT1 level decreased, and by the end of the 3 week it increased again, reaching the initial level. Deficiency of serotonin in the prenatal period caused a significant increase in the level of GAT in the neuropil of the Bötzinger complex in experimental animals at all studied stages of postnatal development. Conclusions. Prenatal deficiency of serotonin leads to a significant increase in the GAT1 level at the early stages of postnatal development, which can lead to a change in the GABA transmission, and, as a result, to a disturbance in the balance of inhibitory and stimulatory effects in the respiratory nuclei.

GABA Transporter-1 (GAT1)-Deficient Mice: Differential Tonic Activation of GABAA Versus GABAB Receptors in the Hippocampus

2003 ◽  
Vol 90 (4) ◽  
pp. 2690-2701 ◽  
Author(s):  
Kimmo Jensen ◽  
Chi-Sung Chiu ◽  
Irina Sokolova ◽  
Henry A. Lester ◽  
Istvan Mody
Keyword(s):  
Gaba Release ◽  
Gabab Receptors ◽  
Acid Decarboxylase ◽  
Wild Type ◽  
Gaba Transporter ◽  
Inhibitory Neurotransmitter ◽  
Gaba Transporters ◽  
Gaba Transporter 1 ◽  
Glutamic Acid Decarboxylase 65 ◽  
Deficient Mice

After its release from interneurons in the CNS, the major inhibitory neurotransmitter GABA is taken up by GABA transporters (GATs). The predominant neuronal GABA transporter GAT1 is localized in GABAergic axons and nerve terminals, where it is thought to influence GABAergic synaptic transmission, but the details of this regulation are unclear. To address this issue, we have generated a strain of GAT1-deficient mice. We observed a large increase in a tonic postsynaptic hippocampal GABAA receptor-mediated conductance. There was little or no change in the waveform or amplitude of spontaneous inhibitory postsynaptic currents (IPSCs) or miniature IPSCs. In contrast, the frequency of quantal GABA release was one-third of wild type (WT), although the densities of GABAA receptors, GABAB receptors, glutamic acid decarboxylase 65 kDa, and vesicular GAT were unaltered. The GAT1-deficient mice lacked a presynaptic GABAB receptor tone, present in WT mice, which reduces the frequency of spontaneous IPSCs. We conclude that GAT1 deficiency leads to enhanced extracellular GABA levels resulting in an overactivation of GABAA receptors responsible for a postsynaptic tonic conductance. Chronically elevated GABA levels also downregulate phasic GABA release and reduce presynaptic signaling via GABAB receptors thus causing an enhanced tonic and a diminished phasic inhibition.

scholarly journals Tonic Extrasynaptic GABAA Receptor Currents Control Gonadotropin-Releasing Hormone Neuron Excitability in the Mouse

Endocrinology ◽  
2011 ◽  
Vol 152 (4) ◽  
pp. 1551-1561 ◽  
Author(s):  
Janardhan P. Bhattarai ◽  
Seon Ah Park ◽  
Jin Bong Park ◽  
So Yeong Lee ◽  
Allan E. Herbison ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Gabaa Receptors ◽  
Brain Slice ◽  
Resting Membrane Potential ◽  
Receptor Signaling ◽  
Gaba Transporter ◽  
Gnrh Neurons ◽  
Inward Currents ◽  
Synaptic Receptors ◽  
Tonic Current

Abstract It is well established that the GABAA receptor plays an important role in regulating the electrical excitability of GnRH neurons. Two different modes of GABAA receptor signaling exist: one mediated by synaptic receptors generating fast (phasic) postsynaptic currents and the other mediated by extrasynaptic receptors generating a persistent (tonic) current. Using GABAA receptor antagonists picrotoxin, bicuculline methiodide, and gabazine, which differentiate between phasic and tonic signaling, we found that ∼50% of GnRH neurons exhibit an approximately 15-pA tonic GABAA receptor current in the acute brain slice preparation. The blockade of either neuronal (NO711) or glial (SNAP-5114) GABA transporter activity within the brain slice revealed the presence of tonic GABA signaling in ∼90% of GnRH neurons. The GABAA receptor δ subunit is only found in extrasynaptic GABAA receptors. Using single-cell RT-PCR, GABAA receptor δ subunit mRNA was identified in GnRH neurons and the δ subunit–specific agonist 4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridin-3-ol was found to activate inward currents in GnRH neurons. Perforated-patch clamp studies showed that 4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridin-3-ol exerted the same depolarizing or hyperpolarizing effects as GABA on juvenile and adult GnRH neurons and that tonic GABAA receptor signaling regulates resting membrane potential. Together, these studies reveal the presence of a tonic GABAA receptor current in GnRH neurons that controls their excitability. The level of tonic current is dependent, in part, on neuronal and glial GABA transporter activity and mediated by extrasynaptic δ subunit–containing GABAA receptors.

Abstract WMP106: Reversal of Tonic Inhibition Contributes to Recovery of Synaptic Function After Transient Focal Cerebral Ischemia

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
James E Orfila ◽  
Robert M Dietz ◽  
Himmat Grewal ◽  
Takeru Shimizu ◽  
Frank F Strnad ◽  
...  
Keyword(s):  
Western Blot ◽  
Blot Analysis ◽  
Gabaa Receptors ◽  
Western Blot Analysis ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
The United States ◽  
Synaptic Function ◽  
Gaba Transporter ◽  
Adult Mice

Introduction: Ischemic stroke is the fourth leading cause of death in the United States and is increasingly being recognized as a disease that occurs in people of all ages, not just the elderly. Studies suggest that the immature developing brain may have a greater degree of plasticity compared to the adult, thereby enhancing functional recovery to a greater extent during development. Hypothesis: Pediatric mice exhibit greater recovery from hippocampal synaptic function following experimental stroke than adults. Methods: Extracellular field recordings of CA1 neurons were performed in acute hippocampal slices prepared at, 7 or 30 days after recovery from middle cerebral artery occlusion (MCAO). A behavioral fear conditioning paradigm was done to evaluate contextual memory in both pediatric and adult mice 30 days after MCAO. α5 GABAA receptors and GABA transporter expression was evaluated by western blot analysis. Results: In adult mice following MCAO, hippocampal long-term potentiation (LTP), defined as an increase in synaptic strength, remained impaired for at least 30 days in the ipsilateral and contralateral, non-injured hemisphere. However, in pediatric mice following MCAO, LTP was only impaired in the ipsilateral side 7 days after MCAO and showed full recovery of synaptic function at 30 days. Behavioral data confirmed these data, showing that only adult mice displayed memory deficits 30 days after MCAO. L655,708 (100nM), an inverse agonist selective for α5 GABAA receptors, rescued LTP in acute slices in both pediatric and adult mice at all-time points tested. Western blot analysis failed to identify any changes in α5 GABAA receptors or GABA transporter (GAT1 or GAT3) levels after MCAO. Conclusion: The present study demonstrates that transient focal ischemia causes functional impairment in the hippocampus and that recovery of behavioral and synaptic function is more robust in the young brain. In addition, inhibition of tonic GABA activity rescues synaptic function, indicating that targeting of excessive GABA activity may provide a therapeutic approach to improve cognitive recovery after stroke.

scholarly journals Pharmacological Characterization of a Betaine/GABA Transporter 1 (BGT1) Inhibitor Displaying an Unusual Biphasic Inhibition Profile and Anti-seizure Effects

2020 ◽  
Vol 45 (7) ◽  
pp. 1551-1565
Author(s):  
Maria E. K. Lie ◽  
Stefanie Kickinger ◽  
Jonas Skovgaard-Petersen ◽  
Gerhard F. Ecker ◽  
Rasmus P. Clausen ◽  
...  
Keyword(s):  
Gaba Transporter ◽  
Pharmacological Characterization ◽  
Gaba Transporter 1

scholarly journals Dynamics of Dynamin-Related Protein 1 in Alzheimer’s Disease and Other Neurodegenerative Diseases

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 961 ◽  
Author(s):  
Darryll Oliver ◽  
P. Reddy
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Mouse Models ◽  
Cell Cultures ◽  
Neuronal Damage ◽  
Mitochondrial Dynamics ◽  
Neurological Diseases ◽  
Large Family ◽  
Related Protein

The purpose of this article is to highlight the role of dynamin-related protein 1 (Drp1) in abnormal mitochondrial dynamics, mitochondrial fragmentation, autophagy/mitophagy, and neuronal damage in Alzheimer’s disease (AD) and other neurological diseases, including Parkinson’s, Huntington’s, amyotrophic lateral sclerosis, multiple sclerosis, diabetes, and obesity. Dynamin-related protein 1 is one of the evolutionarily highly conserved large family of GTPase proteins. Drp1 is critical for mitochondrial division, size, shape, and distribution throughout the neuron, from cell body to axons, dendrites, and nerve terminals. Several decades of intense research from several groups revealed that Drp1 is enriched at neuronal terminals and involved in synapse formation and synaptic sprouting. Different phosphorylated forms of Drp1 acts as both increased fragmentation and/or increased fusion of mitochondria. Increased levels of Drp1 were found in diseased states and caused excessive fragmentation of mitochondria, leading to mitochondrial dysfunction and neuronal damage. In the last two decades, several Drp1 inhibitors have been developed, including Mdivi-1, Dynasore, P110, and DDQ and their beneficial effects tested using cell cultures and mouse models of neurodegenerative diseases. Recent research using genetic crossing studies revealed that a partial reduction of Drp1 is protective against mutant protein(s)-induced mitochondrial and synaptic toxicities. Based on findings from cell cultures, mouse models and postmortem brains of AD and other neurodegenerative disease, we cautiously conclude that reduced Drp1 is a promising therapeutic target for AD and other neurological diseases.

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