Excessive Astrocytic GABA Causes Cortical Hypometabolism and Impedes Functional Recovery after Subcortical Stroke

Nam, Min‐Ho; Cho, Jongwook; Kwon, Dae‐Hyuk; Park, Jiyoung; Woo, Junsung; Lee, Jung Moo; Lee, Sang‐Won; Ko, Heung Kyu; Won, Woojin; Kim, Ra Gyung; Song, Hanlim; Oh, Soo‐Jin; Choi, Ji Won; Park, Ki Duk; Park, Eun Kyung; Jung, Haejin; Kim, Hyung-Seok; Lee, Min-Cheol; Yun, Mijin; Lee, C. Justin; Kim, Hyoung-Ihl

doi:10.1016/j.celrep.2020.107861

Cited by 46 publications

(61 citation statements)

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“…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). Whether this mechanism underlies GABA release in our model remains to be investigated.…”

Section: Astrocytic Gaba Production and Releasecontrasting

confidence: 79%

“…Our immunohistochemical analysis showed increased immunoreactivity for both GAD and MAO-B, indicating that astrocytic GABA synthesis occurs through multiple routes. Involvement of GAD in the process is at odds with studies reporting that astrocytic GABA production is primarily accomplished by putrescine degradation via MAO-B (22,24,25,33,55). However, decarboxylation of glutamate via astrocytic GAD may represent an epilepsy-specific mechanism, triggered by the excessive astrocytic glutamate uptake during neuronal hyperactivity.…”

Section: Astrocytic Gaba Production and Releasementioning

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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Section: Astrocytic Gaba Production and Releasecontrasting

confidence: 79%

Section: Astrocytic Gaba Production and Releasementioning

confidence: 99%

Section: Astrocytic Gaba Production and Releasementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Astrocytic GABA Accumulation in Experimental Temporal Lobe Epilepsy

et al. 2020

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“…We previously reported that MAOB is responsible for astrocytic GABA synthesis, which accounts for tonic inhibition of neighboring neurons in various brain regions, including the hippocampus, cortex, cerebellum, and SNpc [ 10 , 16 - 20 ]. Particularly, we demonstrated that the MAOB-dependent tonic inhibition of DA neurons was aberrantly increased in the SNpc of both PD patients and animal PD models [ 10 ].…”

Section: Resultsmentioning

confidence: 99%

The Pathological Role of Astrocytic MAOB in Parkinsonism Revealed by Genetic Ablation and Over-expression of MAOB

Heo

Lee

et al. 2021

Exp Neurobiol

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The cause of Parkinson’s disease has been traditionally believed to be the dopaminergic neuronal death in the substantia nigra pars compacta (SNpc). This traditional view has been recently challenged by the proposal that reactive astrocytes serve as key players in the pathology of Parkinson’s disease through excessive GABA release. This aberrant astrocytic GABA is synthesized by the enzymatic action of monoamine oxidase B (MAOB), whose pharmacological inhibition and gene-silencing are reported to significantly alleviate parkinsonian motor symptoms in animal models of Parkinson’s disease. However, whether genetic ablation and over-expression of MAOB can bidirectionally regulate parkinsonian motor symptoms has not been tested. Here we demonstrate that genetic ablation of MAOB blocks the MPTP-induced augmentation of astrocytic GABA-mediated tonic inhibition of neighboring dopaminergic neurons as well as parkinsonian motor symptoms, indicating the necessity of MAOB for parkinsonian motor symptoms. Furthermore, we demonstrate that GFAP-MAOB transgenic mice, in which MAOB is over-expressed under the GFAP promoter for astrocyte-specific over-expression, display exacerbated MPTP-induced tonic inhibition and parkinsonian motor symptoms compared to wild-type mice, indicating the importance of astrocytic MAOB for parkinsonian motor symptoms. Our study provides genetic pieces of evidence for the causal link between the pathological role of astrocytic MAOB-dependent tonic GABA synthesis and parkinsonian motor symptoms.

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Diagnostic and therapeutic potential of tonic gamma‐aminobutyric acid from reactive astrocytes in brain diseases

Koh,

Lee

2024

Clinical & Translational Med

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Diagnostic and therapeutic potential of tonic gamma-aminobutyric acid from reactive astrocytes in brain diseasesDear Editor, Gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain, serves as a cornerstone in modulating neuronal activity and maintaining cognitive functions. Its role extends beyond fast-acting phasic inhibition, as slow-acting tonic GABA inhibition, mediated by extrasynaptic GABA A receptors, responds to ambient GABA levels (i.e. GABA tone), significantly influencing synaptic plasticity, learning and memory, and sensory processing. 1 Dysregulation of tonic GABA inhibition in a range of neurological and psychiatric diseases is associated with cognitive decline, motor symptoms, and other functional impairments, highlighting the potentially broad impact of GABA tone across various diseases. One of the common cellular responses in pathological conditions is the emergence of reactive astrocytes, 2 often accompanied by upregulation of monoamine oxidase B (MAO-B) expression and increased GABA synthesis (Figure 1A), thus affecting neighbouring neurons through tonic inhibition. 3 Here, we present the impact of pathological GABA tone and propose its therapeutic and diagnostic targets for clinical applications.Astrocytes once thought to be mere support cells, emerge as key players in the regulation of GABA tone through various mechanisms of GABA synthesis, release, and clearance. 1 These cells are strategically positioned to interface closely with neurons, allowing them to effectively regulate GABA tone in the extrasynaptic space. This role becomes particularly crucial in a range of pathological conditions, such as Alzheimer's 3-5 and Parkinson's diseases. 6,7 In these conditions, astrocytes become reactive, exhibiting increased MAO-B expression and enhanced GABA synthesis, which contributes to an elevated GABA tone and leads to pathological symptoms. This phenomenon is not limited to Alzheimer's and Parkinson's disease but is also observed in stroke, 8 depression, 9 obesity, 10 and potentially extends to conditions like post-traumatic stress disorderThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Excessive Astrocytic GABA Causes Cortical Hypometabolism and Impedes Functional Recovery after Subcortical Stroke

Cited by 46 publications

References 50 publications

Astrocytic GABA Accumulation in Experimental Temporal Lobe Epilepsy

Astrocytic GABA Accumulation in Experimental Temporal Lobe Epilepsy

The Pathological Role of Astrocytic MAOB in Parkinsonism Revealed by Genetic Ablation and Over-expression of MAOB

Diagnostic and therapeutic potential of tonic gamma‐aminobutyric acid from reactive astrocytes in brain diseases

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