Crucial Role for Astrocytes in Epilepsy

Bedner, Peter; Steinhäuser, Christian

doi:10.4199/c00135ed1v01y201507ngl008

Cited by 3 publications

(5 citation statements)

References 286 publications

(262 reference statements)

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“…Indeed, GABA accumulation in reactive astrocytes has been observed in different brain pathologies, including Alzheimer's disease, Parkinson's disease, stroke and epilepsy (22)(23)(24)(25), suggesting that it represents a general feature of the astrocytic reaction. Increasing evidence suggests that astrocyte changes associated with astrogliosis play a detrimental role in epileptogenesis (51)(52)(53), a view that is not compatible with an assumed protective effect of astrocytic GABA release. On the other hand, reactive astrocytes might play a dual role in CNS pathologies (54), and whether they exert pro-or antiepileptic effects in epilepsy probably depends on a number of factors, including etiology, timing and severity of epilepsy as well as environmental conditions and interactions with other factors (e.g., inflammatory mediators).…”

Section: Astrocytic Gaba Production and Releasementioning

confidence: 99%

Astrocytic GABA Accumulation in Experimental Temporal Lobe Epilepsy

et al. 2020

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An imbalance of excitation and inhibition has been associated with the pathophysiology of epilepsy. Loss of GABAergic interneurons and/or synaptic inhibition has been shown in various epilepsy models and in human epilepsy. Despite this loss, several studies reported preserved or increased tonic GABAA receptor-mediated currents in epilepsy, raising the question of the source of the inhibitory transmitter. We used the unilateral intracortical kainate mouse model of temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS) to answer this question. In our model we observed profound loss of interneurons in the sclerotic hippocampal CA1 region and dentate gyrus already 5 days after epilepsy induction. Consistent with the literature, the absence of interneurons caused no reduction of tonic inhibition of CA1 pyramidal neurons. In dentate granule cells the inhibitory currents were even increased in epileptic tissue. Intriguingly, immunostaining of brain sections from epileptic mice with antibodies against GABA revealed strong and progressive accumulation of the neurotransmitter in reactive astrocytes. Pharmacological inhibition of the astrocytic GABA transporter GAT3 did not affect tonic inhibition in the sclerotic hippocampus, suggesting that this transporter is not responsible for astrocytic GABA accumulation or release. Immunostaining further indicated that both decarboxylation of glutamate and putrescine degradation accounted for the increased GABA levels in reactive astrocytes. Together, our data provide evidence that the preserved tonic inhibitory currents in the epileptic brain are mediated by GABA overproduction and release from astrocytes. A deeper understanding of the underlying mechanisms may lead to new strategies for antiepileptic drug therapy.

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Section: Astrocytic Gaba Production and Releasementioning

confidence: 99%

Astrocytic GABA Accumulation in Experimental Temporal Lobe Epilepsy

et al. 2020

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“…Another essential role of astrocytes is maintaining potassium homeostasis. This is achieved by either net uptake of potassium or potassium spatial buffering ( Macaulay and Zeuthen, 2012 ; Bedner and Steinhäuser, 2014 ; Cheung et al, 2015 ). The net uptake of potassium involves a variety of cotransporters that includes the Na + /K + pumps as well as the Na + /K + /Cl - cotransporters ( Macaulay and Zeuthen, 2012 ; Bedner and Steinhäuser, 2014 ).…”

Section: Potential Mechanisms Underlying Impaired Ltp In Aqp4 Ko Micementioning

confidence: 99%

“…This is achieved by either net uptake of potassium or potassium spatial buffering ( Macaulay and Zeuthen, 2012 ; Bedner and Steinhäuser, 2014 ; Cheung et al, 2015 ). The net uptake of potassium involves a variety of cotransporters that includes the Na + /K + pumps as well as the Na + /K + /Cl - cotransporters ( Macaulay and Zeuthen, 2012 ; Bedner and Steinhäuser, 2014 ). In the spatial potassium buffering model ( Orkand et al, 1966 ) extracellular potassium is taken up by Kir4.1 and redistributed to adjacent astrocytes via gap junctions ( Bedner and Steinhäuser, 2014 ; Cheung et al, 2015 ).…”

Section: Potential Mechanisms Underlying Impaired Ltp In Aqp4 Ko Micementioning

confidence: 99%

“…The net uptake of potassium involves a variety of cotransporters that includes the Na + /K + pumps as well as the Na + /K + /Cl - cotransporters ( Macaulay and Zeuthen, 2012 ; Bedner and Steinhäuser, 2014 ). In the spatial potassium buffering model ( Orkand et al, 1966 ) extracellular potassium is taken up by Kir4.1 and redistributed to adjacent astrocytes via gap junctions ( Bedner and Steinhäuser, 2014 ; Cheung et al, 2015 ). Therefore, potassium dysregulation could also possibly explain the impairment in synaptic potentiation seen in AQP4-null animals.…”

Section: Potential Mechanisms Underlying Impaired Ltp In Aqp4 Ko Micementioning

confidence: 99%

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The Role of Astrocytic Aquaporin-4 in Synaptic Plasticity and Learning and Memory

Szu

Binder

2016

Front. Integr. Neurosci.

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Aquaporin-4 (AQP4) is the predominant water channel expressed by astrocytes in the central nervous system (CNS). AQP4 is widely expressed throughout the brain, especially at the blood-brain barrier where AQP4 is highly polarized to astrocytic foot processes in contact with blood vessels. The bidirectional water transport function of AQP4 suggests its role in cerebral water balance in the CNS. The regulation of AQP4 has been extensively investigated in various neuropathological conditions such as cerebral edema, epilepsy, and ischemia, however, the functional role of AQP4 in synaptic plasticity, learning, and memory is only beginning to be elucidated. In this review, we explore the current literature on AQP4 and its influence on long term potentiation (LTP) and long term depression (LTD) in the hippocampus as well as the potential relationship between AQP4 and in learning and memory. We begin by discussing recent in vitro and in vivo studies using AQP4-null and wild-type mice, in particular, the impairment of LTP and LTD observed in the hippocampus. Early evidence using AQP4-null mice have suggested that impaired LTP and LTD is brain-derived neurotrophic factor dependent. Others have indicated a possible link between defective LTP and the downregulation of glutamate transporter-1 which is rescued by chronic treatment of β-lactam antibiotic ceftriaxone. Furthermore, behavioral studies may shed some light into the functional role of AQP4 in learning and memory. AQP4-null mice performances utilizing Morris water maze, object placement tests, and contextual fear conditioning proposed a specific role of AQP4 in memory consolidation. All together, these studies highlight the potential influence AQP4 may have on long term synaptic plasticity and memory.

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“…Classification models, in particular, have been utilized extensively in the understanding of MCI. These models can help us to understand patterns in the behavior of data in terms of diagnosing MCI, specifically in the consideration of key features pertaining to a diagnosis of impairment [ 9 , 10 ] or predicting the progression of the impairment [ 11 ]. Furthermore, models have been developed to apply a more objective approach to the MCI diagnosis [ 12 ], not to undermine but rather to support a clinician’s analysis [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Identifying Key Predictors of Cognitive Dysfunction in Older People Using Supervised Machine Learning Techniques: Observational Study

Rankin¹,

Black²,

Flanagan³

et al. 2020

JMIR Med Inform

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Background Machine learning techniques, specifically classification algorithms, may be effective to help understand key health, nutritional, and environmental factors associated with cognitive function in aging populations. Objective This study aims to use classification techniques to identify the key patient predictors that are considered most important in the classification of poorer cognitive performance, which is an early risk factor for dementia. Methods Data were used from the Trinity-Ulster and Department of Agriculture study, which included detailed information on sociodemographic, clinical, biochemical, nutritional, and lifestyle factors in 5186 older adults recruited from the Republic of Ireland and Northern Ireland, a proportion of whom (987/5186, 19.03%) were followed up 5-7 years later for reassessment. Cognitive function at both time points was assessed using a battery of tests, including the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), with a score <70 classed as poorer cognitive performance. This study trained 3 classifiers—decision trees, Naïve Bayes, and random forests—to classify the RBANS score and to identify key health, nutritional, and environmental predictors of cognitive performance and cognitive decline over the follow-up period. It assessed their performance, taking note of the variables that were deemed important for the optimized classifiers for their computational diagnostics. Results In the classification of a low RBANS score (<70), our models performed well (F1 score range 0.73-0.93), all highlighting the individual’s score from the Timed Up and Go (TUG) test, the age at which the participant stopped education, and whether or not the participant’s family reported memory concerns to be of key importance. The classification models performed well in classifying a greater rate of decline in the RBANS score (F1 score range 0.66-0.85), also indicating the TUG score to be of key importance, followed by blood indicators: plasma homocysteine, vitamin B6 biomarker (plasma pyridoxal-5-phosphate), and glycated hemoglobin. Conclusions The results suggest that it may be possible for a health care professional to make an initial evaluation, with a high level of confidence, of the potential for cognitive dysfunction using only a few short, noninvasive questions, thus providing a quick, efficient, and noninvasive way to help them decide whether or not a patient requires a full cognitive evaluation. This approach has the potential benefits of making time and cost savings for health service providers and avoiding stress created through unnecessary cognitive assessments in low-risk patients.

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Crucial Role for Astrocytes in Epilepsy

Cited by 3 publications

References 286 publications

Astrocytic GABA Accumulation in Experimental Temporal Lobe Epilepsy

Astrocytic GABA Accumulation in Experimental Temporal Lobe Epilepsy

The Role of Astrocytic Aquaporin-4 in Synaptic Plasticity and Learning and Memory

Identifying Key Predictors of Cognitive Dysfunction in Older People Using Supervised Machine Learning Techniques: Observational Study

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