GABA tone regulation and its cognitive functions in the brain

Koh, Won‐Jung; Kwak, Hankyul; Cheong, Eunji; Lee, C. Justin

doi:10.1038/s41583-023-00724-7

Cited by 41 publications

(24 citation statements)

References 198 publications

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“…79 Excess α5GABA A R activity has been associated with cognitive or motor deficits due to ischemic stroke, 80,81 Alzheimer disease, 82 traumatic brain injury, and Down syndrome. 4,41,83,84 Conversely, we found that deficits in α5GABA A Rs in mice have been associated with autism-like behaviors. 85,86 Positive emission tomography studies of humans with autism spectrum disorder performed by others provided initial evidence of an α5GABA A R deficit, 87 and positive allosteric modulators for these receptors may mitigate the cognitive deficits associated with autism spectrum disorder.…”

Section: Properties Of Extrasynaptic Gaba a Receptors Your Data Caref...mentioning

confidence: 65%

“…3,[37][38][39] Also, by understanding how anesthetic drugs impair memory, we might gain insights into the cause of memory deficits associated with conditions like traumatic brain injury 4 and Alzheimer disease. 40,41 We started by searching for synaptic GABA A receptors that were modified by low, amnestic concentrations of propofol and the classic benzodiazepine midazolam. Using a mouse model, we performed patch clamp electrophysiologic recordings with cultured neurons and brain slices from the hippocampus-a brain region that plays a key role in learning and memory processes.…”

mentioning

confidence: 99%

“…3,37–39 Also, by understanding how anesthetic drugs impair memory, we might gain insights into the cause of memory deficits associated with conditions like traumatic brain injury 4 and Alzheimer disease. 40,41…”

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confidence: 99%

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Discovering the Intriguing Properties of Extrasynaptic γ-Aminobutyric Acid Type A Receptors

Orser

2024

Anesthesiology

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Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by α5 subunit-containing γ-aminobutyric acid type A receptors. By Caraiscos VB, Elliott EM, You-Ten KE, Cheng VY, Belelli D, Newell JG, Jackson MF, Lambert JJ, Rosahl TW, Wafford KA, MacDonald JF, Orser BA. Proc Natl Acad Sci U S A 2004; 101:3662–7. Reprinted with permission. In this Classic Paper Revisited, the author recounts the scientific journey leading to a report published in the Proceedings of the National Academy of Sciences (PNAS) and shares several personal stories from her formative years and “research truths” that she has learned along the way. Briefly, the principal inhibitory neurotransmitter in the brain, γ-aminobutyric acid (GABA), was conventionally thought to regulate cognitive processes by activating synaptic GABA type A (GABAA) receptors and generating transient inhibitory synaptic currents. However, the author’s laboratory team discovered a novel nonsynaptic form of tonic inhibition in hippocampal pyramidal neurons, mediated by extrasynaptic GABAA receptors that are pharmacologically distinct from synaptic GABAA receptors. This tonic current is highly sensitive to most general anesthetics, including sevoflurane and propofol, and likely contributes to the memory-blocking properties of these drugs. Before the publication in PNAS, the subunit composition of GABAA receptors that generate the tonic current was unknown. The team’s research showed that GABAA receptors containing the α5 subunit (α5GABAARs) generated the tonic inhibitory current in hippocampal neurons. α5GABAARs are highly sensitive to GABA, desensitize slowly, and are thus well suited for detecting low, persistent, ambient concentrations of GABA in the extracellular space. Interest in α5GABAARs has surged since the PNAS report, driven by their pivotal roles in cognitive processes and their potential as therapeutic targets for treating various neurologic disorders.

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Section: Properties Of Extrasynaptic Gaba a Receptors Your Data Caref...mentioning

confidence: 65%

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Discovering the Intriguing Properties of Extrasynaptic γ-Aminobutyric Acid Type A Receptors

Orser

2024

Anesthesiology

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“…Astrocytes are both GABAergic and GABAceptive, playing an important role in GABA metabolism in the brain (42,43). Therefore, the significant increase in astrocytic GABA upon hM3Dq-DREADD activation of interneurons suggests enhanced astrocytic uptake of GABA that is increasingly released from activated interneurons.…”

Section: Discussionmentioning

confidence: 99%

“…While chemogenetic manipulation of interneuron activity appeared to have no effect upon astrogliosis, considering the recent evidence suggesting astrocytic regulation of GABA (42,43), we next explored whether astrocytic GABA expression is altered in the brain of Cln2 R207X/R207X mice and whether that can be affected by chemogenetic manipulation of interneuron activity. Coimmunostaining for GFAP and GABA revealed pronounced co-localization of these two signals within CPu, S1BF, and VPM/VPL as early as 12 weeks (3 months) of age (Figure S4), suggesting increased levels of GABA in GFAP-positive reactive astrocytes.…”

Section: Chemogenetic Activation Of Interneurons Alters Microglial Ac...mentioning

confidence: 99%

GABAergic interneurons contribute to the fatal seizure phenotype of CLN2 disease mice

Takahashi,

Rensing,

Eultgen

et al. 2024

Preprint

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GABAergic interneuron deficits have been implicated in the epileptogenesis of multiple neurological diseases. While epileptic seizures are a key clinical hallmark of CLN2 disease, a childhood-onset neurodegenerative lysosomal storage disorder caused by a deficiency of tripeptidyl peptidase 1 (TPP1), the etiology of these seizures remains elusive. Given thatCln2R207X/R207Xmice display fatal spontaneous seizures and an early loss of several cortical interneuron populations, we hypothesized that those two events might be causally related. To address this hypothesis, we first generated an inducible transgenic mouse expressing lysosomal membrane-tethered TPP1 (TPP1LAMP1) on theCln2R207X/R207Xgenetic background to study the cell-autonomous effects of cell-type-specific TPP1 deficiency. We crossed the TPP1LAMP1 mice withVgat-Cremice to introduce interneuron-specific TPP1 deficiency.Vgat-Cre; TPP1LAMP1 mice displayed storage material accumulation in several interneuron populations both in cortex and striatum, and increased susceptibility to die after PTZ-induced seizures. Secondly, to test the role of GABAergic interneuron activity in seizure progression, we selectively activated these cells inCln2R207X/R207Xmice using Designer Receptor Exclusively Activated by Designer Drugs (DREADDs) inVgat-Cre: Cln2R207X/R207Xmice. EEG monitoring revealed that DREADD-mediated activation of interneurons via chronic deschloroclozapine administration accelerated the onset of spontaneous seizures and seizure-associated death inVgat-Cre: Cln2R207X/R207Xmice, suggesting that modulating interneuron activity can exert influence over epileptiform abnormalities in CLN2 disease. Taken together, these results provide new mechanistic insights into the underlying etiology of seizures and premature death that characterize CLN2 disease.

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Nano‐Enabled Intracellular Bursting of Calcium and Retinoic Acid Regulates Dopaminergic Neuronal Differentiation of NSCs for Parkinson's Disease Therapy

Zhang,

Liu,

Zhou

et al. 2024

Adv Funct Materials

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Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by dopaminergic neuron degeneration. Neural stem cell (NSC) therapy offers promise for replacing these neurons and restoring neural function. However, directing NSCs to become dopaminergic neurons is challenging. Retinoic acid (RA) is a potential regulator, but its insolubility in water limits its use in PD therapy. Herein, nanonizing RA with calcium acetate to create calcium‐retinoic acid nanoparticles (Ca‐RA NPs) is proposed. These nanoparticles can be internalized by NSCs and then dissociated in the acidic environment of lysosomes to lead to a burst of Ca2+ and RA. In vitro results showed that the intracellular bursting of Ca2+ and RA accelerated neuronal differentiation and maturation by 5–10 days compared to spontaneous NSC differentiation. Importantly, Ca‐RA NPs uniquely directed NSCs to dopaminergic neurons, involving the interaction between the calcium ion‐mediated MAPK signaling pathway and the RA‐mediated RA signaling pathway. Animal experiments further validated the efficacy of Ca‐RA‐coated NSCs in restoring motor and cognitive functions in PD mice by rapidly forming dopaminergic neural circuits. Given that both RA and calcium acetate are approved by the FDA, this strategy has the potential for translation into a clinical treatment approach for stem cell therapy of PD.

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GABA tone regulation and its cognitive functions in the brain

Cited by 41 publications

References 198 publications

Discovering the Intriguing Properties of Extrasynaptic γ-Aminobutyric Acid Type A Receptors

Discovering the Intriguing Properties of Extrasynaptic γ-Aminobutyric Acid Type A Receptors

GABAergic interneurons contribute to the fatal seizure phenotype of CLN2 disease mice

Nano‐Enabled Intracellular Bursting of Calcium and Retinoic Acid Regulates Dopaminergic Neuronal Differentiation of NSCs for Parkinson's Disease Therapy

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