GABAergic signaling to astrocytes in the prefrontal cortex sustains goal-directed behaviors

Mederos, Sara; Sánchez‐Puelles, Cristina; Esparza, Julio; Valero, Manuel; Ponomarenko, Alexey; Perea, Gertrudis

doi:10.1038/s41593-020-00752-x

Cited by 108 publications

(110 citation statements)

References 69 publications

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“…GABAergic interneurons play a critical role in higher brain functions, and signaling from interneurons to normally sustains important cortical information processing and complex behaviors [35]. In an epileptic network with extensive aberrant neuronal sprouting and altered ionic mechanisms, the effect of VGB on GABAergic activity probably makes it impossible for GABAergic interneurons to exert normal signaling and behavioral responses.…”

Section: Discussionmentioning

confidence: 99%

The Discordance between Network Excitability and Cognitive Performance Following Vigabatrin Treatment during Epileptogenesis

Lai

Huang

2021

Life

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Vigabatrin (VGB), a potent selective γ-aminobutyric acid transaminase (GABA-T) inhibitor, is an approved non-traditional anti-seizure drug for patients with intractable epilepsy. Nevertheless, its effect on epileptogenesis, and whether this effect is correlated with post-epileptogenic cognitive function remain unclear. Based on lithium-pilocarpine-induced seizure modeling, we evaluated the effect of VGB on epileptogenesis and neuronal damage following status epilepticus in Sprague–Dawley rats. Cognitive evaluations were performed with the aid of inhibitory avoidance testing. We found that VGB could interrupt epileptogenesis by reducing spontaneous recurrent seizures, hippocampal neuronal damage, and chronic mossy fiber sprouting. Nevertheless, VGB did not help with the retention of cognitive performance. Our findings suggest that further research into the role of VGB in epileptogenesis and the treatment of epilepsy in clinical practice is warranted.

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Section: Discussionmentioning

confidence: 99%

The Discordance between Network Excitability and Cognitive Performance Following Vigabatrin Treatment during Epileptogenesis

Lai

Huang

2021

Life

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“…GABA released from astrocytes exert a tonic inhibitory influence onto cerebellar granule neurons and striatal medium spiny neurons via the activation of GABA A receptors [159]. In the prefrontal cortex, on the other hand, astrocytic GABA interacts with GABAergic interneurons via GABA B receptors [160]. Under normal conditions, hippocampal astrocytes contain very little GABA [161], but diseased astrocytes around amyloid plaques become reactive and aberrantly and abundantly produce and release GABA via the anion channel bestrophin 1 (BEST1) [161] (Figure 3).…”

Section: Altered Gaba Release From Astrocytes In Admentioning

confidence: 99%

Dysregulation of Astrocyte–Neuronal Communication in Alzheimer’s Disease

Nanclares

Baraibar

Araque

et al. 2021

IJMS

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Recent studies implicate astrocytes in Alzheimer’s disease (AD); however, their role in pathogenesis is poorly understood. Astrocytes have well-established functions in supportive functions such as extracellular ionic homeostasis, structural support, and neurovascular coupling. However, emerging research on astrocytic function in the healthy brain also indicates their role in regulating synaptic plasticity and neuronal excitability via the release of neuroactive substances named gliotransmitters. Here, we review how this “active” role of astrocytes at synapses could contribute to synaptic and neuronal network dysfunction and cognitive impairment in AD.

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“…A recent study explored the circuit and behavioral consequences of astrocyte-specific knockout of GABA B receptors in prefrontal cortex ( Mederos et al, 2021 ). They also found a reduction of low gamma oscillations in active awake mice, but not in resting mice.…”

Section: Consequences Of Astroglia-specific Deletion Of Endogenous Plasma Membrane Proteinsmentioning

confidence: 99%

“…Low gamma oscillations may reflect synchronization of the neuronal population and has been associated with working memory processing in prefrontal cortex ( Buzśaki and Wang, 2012 ). Indeed, mice lacking GABA B receptors in prefrontal cortex astrocytes have difficulty making correct decisions during the T-maze alternating behavioral task, a paradigm testing working memory performance ( Mederos et al, 2021 ). A more detailed cellular analysis of the circuit function revealed that astrocyte GABA B receptors, IP 3 R2-dependently, potentiate parvalbumin-positive interneuron-driven inhibitory postsynaptic currents in local neurons.…”

Section: Consequences Of Astroglia-specific Deletion Of Endogenous Plasma Membrane Proteinsmentioning

confidence: 99%

“…A more detailed cellular analysis of the circuit function revealed that astrocyte GABA B receptors, IP 3 R2-dependently, potentiate parvalbumin-positive interneuron-driven inhibitory postsynaptic currents in local neurons. Using astrocyte-specific overexpression of melanopsin 1 for optical control of G q protein-coupled receptor activation exclusively in astrocytes ( Mederos et al, 2019 ), they not only rescued goal-directed behavior in astrocyte-GABA B receptor knockout mice but further enhanced goal-directed behavior in wildtype mice ( Mederos et al, 2021 ). This observation is in contrast with disruptive consequences of astrocyte-specific activation of exogenous Gi protein-coupled receptors in striatal astrocytes, which also enhances Ca 2+ dynamics but leads to hyperactivity of the mice ( Nagai et al, 2019 ).…”

Section: Consequences Of Astroglia-specific Deletion Of Endogenous Plasma Membrane Proteinsmentioning

confidence: 99%

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Potential and Realized Impact of Astroglia Ca2 + Dynamics on Circuit Function and Behavior

Lim

Paukert

2021

Front. Cell. Neurosci.

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Astroglia display a wide range of spontaneous and behavioral state-dependent Ca2+ dynamics. During heightened vigilance, noradrenergic signaling leads to quasi-synchronous Ca2+ elevations encompassing soma and processes across the brain-wide astroglia network. Distinct from this vigilance-associated global Ca2+ rise are apparently spontaneous fluctuations within spatially restricted microdomains. Over the years, several strategies have been pursued to shed light on the physiological impact of these signals including deletion of endogenous ion channels or receptors and reduction of intracellular Ca2+ through buffering, extrusion or inhibition of release. Some experiments that revealed the most compelling behavioral alterations employed chemogenetic and optogenetic manipulations to modify astroglia Ca2+ signaling. However, there is considerable contrast between these findings and the comparatively modest effects of inhibiting endogenous sources of Ca2+. In this review, we describe the underlying mechanisms of various forms of astroglia Ca2+ signaling as well as the functional consequences of their inhibition. We then discuss how the effects of exogenous astroglia Ca2+ modification combined with our knowledge of physiological mechanisms of astroglia Ca2+ activation could guide further refinement of behavioral paradigms that will help elucidate the natural Ca2+-dependent function of astroglia.

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GABAergic signaling to astrocytes in the prefrontal cortex sustains goal-directed behaviors

Cited by 108 publications

References 69 publications

The Discordance between Network Excitability and Cognitive Performance Following Vigabatrin Treatment during Epileptogenesis

The Discordance between Network Excitability and Cognitive Performance Following Vigabatrin Treatment during Epileptogenesis

Dysregulation of Astrocyte–Neuronal Communication in Alzheimer’s Disease

Potential and Realized Impact of Astroglia Ca2 + Dynamics on Circuit Function and Behavior

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