Correction: Corrigendum: Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzheimer’s disease model

Wu, Zheng; Guo, Ziyuan; Gearing, Marla; Chen, Gong

doi:10.1038/ncomms5810

Cited by 7 publications

(5 citation statements)

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“…In our model, initiation of epileptogenesis should therefore be faster and more focal. Our data are not in line with the concept that GABA was released through reversed operation of astrocytic GABA transporters, as suggested earlier (23,34). Recent studies provided evidence that reactive astrocytes in epilepsy and other CNS pathologies release GABA through Best1 anion channels (21,22,24).…”

Section: Astrocytic Gaba Production and Releasecontrasting

confidence: 94%

“…The preserved or aberrantly increased tonic GABA A R currents raised the question of the cellular origin of the transmitter. A number of studies have proposed that GABA produced and released by astrocytes significantly contributes to extrasynaptic GABA levels and tonic inhibition, especially under pathological conditions (22,23,(32)(33)(34). To explore whether astrocytic GABA could account for the maintained/increased tonic currents in our TLE model, we performed immunostaining with antibodies against GABA and GFAP in hippocampal slices at different time points after kainate (5, 14, and 28 dpi) or sham injection (14 dpi).…”

Section: Reactive Astrocytes In the Sclerotic Hippocampus Display Promentioning

confidence: 99%

“…This observation led us to conclude that astrocytic GABA accumulation in the ipsilateral hippocampus is not simply mediated by enhanced uptake from the extracellular space. Since SNAP-5114 had no effect, it is also unlikely that GABA was released from astrocytes through a reversed operation of the glial transporter (23,34,35). Astrocytes can synthesize GABA via decarboxylation of glutamate by glutamate decarboxylase (GAD) or through degradation of putrescine mediated primarily by monoamine oxidase B (MAO-B) (33,36).…”

Section: Astrocytic Gaba Synthesis Rather Than Uptake From the Extracmentioning

confidence: 99%

“…Accumulation was even more pronounced 14 and 28 dpi and positively correlated with GFAP immunoreactivity. 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.…”

Section: Astrocytic Gaba Production and Releasementioning

confidence: 99%

“…However, this hypothesis has difficulty explaining the fact that epileptic seizures are intermittent and relatively rare events even in patients and animals with severe epilepsy, pointing to the existence of a compensatory mechanism that restores the excitation-inhibition balance to a large extent (18)(19)(20). Most recent work suggested that the compensation is accomplished by channel-mediated tonic GABA release from reactive astrocytes (21), a mechanism that was proposed to be relevant also in other neurological disorders, such as Alzheimer's disease, Parkinson's disease or stroke (22)(23)(24)(25). According to this scenario, reactive astrocytes aberrantly overproduce and release GABA, which in turn inhibits neuronal excitability and network activity through activation of high affinity, slowly desensitizing extrasynaptic GABA A receptors (GABA A Rs) (20).…”

Section: Introductionmentioning

confidence: 99%

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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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