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Brain Sciences
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GABA Signaling: Therapeutic Targets for Neurodegenerative and Neurodevelopmental Disorders
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GABA Signaling: Therapeutic Targets for Neurodegenerative and Neurodevelopmental Disorders

A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Neuropharmacology and Neuropathology".

Deadline for manuscript submissions: closed (5 December 2022) | Viewed by 18541

Special Issue Editors

Dr. Enrico Cherubini

E-Mail Website
Guest Editor
European Brain Research Institute (EBRI), Fondazione Rita Levi-Montalcini, 00161 Roma, Italy
Interests: hippocampus; development; synaptic plasticity processes; rhythmogenesis; GABAergic signaling; neurotransmitters; ion channels; neurodevelopmental disorders; epilepsy
Dr. Yehezkel Ben-Ari

E-Mail Website
Guest Editor
Neurochlore, Campus scientifique de Luminy, Bâtiment Beret-Delaage, 163 Route de Luminy, 13288 Marseille CEDEX 09, France
Interests: neurbiology; drug development; developmental disorders

Special Issue Information

Dear Colleagues,

γ-aminobutyric acid (GABA) inhibits adult neurons and depolarizes and excites immature ones due to a developmental shift of the activity of the co-transporters NKCC1 and KCC2, involved in chloride uptake and extrusion, respectively. Indeed, GABA (and glycine) are unique in their capacity to shift the polarity of their actions depending on [Cl-]i levels. Interestingly, in a wide range of brain disorders, there is a reversed reduction and enhanced activity of KCC2 and NKCC1, respectively, leading to depolarizing and often excitatory actions of GABA. These alterations are observed not only in developmental disorders but also in neurodegenerative ones, as well as trauma, infarct, and lesions, suggesting that this is a common reaction of networks to insults. These articles, written by experts in theses domains, highlight the therapeutic potential of restoring GABAergic inhibition and a proper E/I balance in key neuronal circuits of the brain.

We encourage the submission of original research and review articles or short communications in the following (but not limited) topics:

  • GABAergic dysfunctions in animal models of neurodevelopmental and neurodegenerative disorders;
  • GABAergic dysfunctions in the brain of ASD and Alzheimer’s disease (AD) patients;
  • Therapeutic interventions to rescue GABAergic dysfunctions in neurodevelopmental and neurodegenerative disorders;
  • In vivo Studies on patients affected mainly by idiopathic forms of ASDs;
  • Post-mortem analysis of brain tissues from patients affected by ASD or AD;
  • Development of biomarkers for the early diagnosis of ASD and AD;
  • GABAergic circuit dysfunctions in neurodevelopmental and neurodegenerative disorders;
  • Treatments to normalize GABAergic neurotransmission and the E/I balance;
  • Altered GABAergic signaling in memory and cognitive decline in AD patients;
  • Machine learning for diagnosis and for monitoring therapeutic interventions. 

Dr. Enrico Cherubini
Dr. Yehezkel Ben-Ari
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Brain Sciences is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • aminobutyric acid
  • brain development
  • cation-chloride co-transporters
  • E/I balance
  • neuronal circuits
  • Neurodevelopmental and Neurodegenerative Disorders.

Published Papers (6 papers)

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Editorial

Jump to: Research, Review

3 pages, 204 KiB  
Editorial
GABA Signaling: Therapeutic Targets for Neurodegenerative and Neurodevelopmental Disorders
by Enrico Cherubini and Yehezkel Ben-Ari
Brain Sci. 2023, 13(9), 1240; https://doi.org/10.3390/brainsci13091240 - 25 Aug 2023
Viewed by 775
Abstract
This Special Issue, “GABA Signaling: Therapeutic Targets for Neurodegenerative and Neurodevelopmental Disorders”, focuses on a fundamental property of the neurotransmitter γ-aminobutyric acid (GABA), namely its capacity to shift, in particular conditions, from the hyperpolarizing to the depolarizing direction [...] Full article
(This article belongs to the Special Issue GABA Signaling: Therapeutic Targets for Neurodegenerative and Neurodevelopmental Disorders)

Research

Jump to: Editorial, Review

10 pages, 1240 KiB  
Article
Unexpected Effect of IL-1β on the Function of GABAA Receptors in Pediatric Focal Cortical Dysplasia
by Veronica Alfano, Alessia Romagnolo, James D. Mills, Pierangelo Cifelli, Alessandro Gaeta, Alessandra Morano, Angelika Mühlebner, Eleonora Aronica, Eleonora Palma and Gabriele Ruffolo
Brain Sci. 2022, 12(6), 807; https://doi.org/10.3390/brainsci12060807 - 19 Jun 2022
Cited by 4 | Viewed by 1880
Abstract
Focal cortical dysplasia (FCD) type II is an epileptogenic malformation of the neocortex, as well as a leading cause of drug-resistant focal epilepsy in children and young adults. The synaptic dysfunctions leading to intractable seizures in this disease appear to have a tight [...] Read more.
Focal cortical dysplasia (FCD) type II is an epileptogenic malformation of the neocortex, as well as a leading cause of drug-resistant focal epilepsy in children and young adults. The synaptic dysfunctions leading to intractable seizures in this disease appear to have a tight relationship with the immaturity of GABAergic neurotransmission. The likely outcome would include hyperpolarizing responses upon activation of GABAARs. In addition, it is well-established that neuroinflammation plays a relevant role in the pathogenesis of FCD type II. Here, we investigated whether IL-1β, a prototypical pro-inflammatory cytokine, can influence GABAergic neurotransmission in FCD brain tissues. To this purpose, we carried out electrophysiological recordings on Xenopus oocytes transplanted with human tissues and performed a transcriptomics analysis. We found that IL-1β decreases the GABA currents amplitude in tissue samples from adult individuals, while it potentiates GABA responses in samples from pediatric cases. Interestingly, these cases of pediatric FCD were characterized by a more depolarized EGABA and an altered transcriptomics profile, that revealed an up-regulation of chloride cotransporter NKCC1 and IL-1β. Altogether, these results suggest that the neuroinflammatory processes and altered chloride homeostasis can contribute together to increase the brain excitability underlying the occurrence of seizures in these children. Full article
(This article belongs to the Special Issue GABA Signaling: Therapeutic Targets for Neurodegenerative and Neurodevelopmental Disorders)
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Review

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23 pages, 4216 KiB  
Review
Quantifying GABA in Addiction: A Review of Proton Magnetic Resonance Spectroscopy Studies
by Claire Shyu, Sofia Chavez, Isabelle Boileau and Bernard Le Foll
Brain Sci. 2022, 12(7), 918; https://doi.org/10.3390/brainsci12070918 - 13 Jul 2022
Cited by 7 | Viewed by 3094
Abstract
Gamma-aminobutyric acid (GABA) signaling plays a crucial role in drug reward and the development of addiction. Historically, GABA neurochemistry in humans has been difficult to study due to methodological limitations. In recent years, proton magnetic resonance spectroscopy (1H-MRS, MRS) has emerged [...] Read more.
Gamma-aminobutyric acid (GABA) signaling plays a crucial role in drug reward and the development of addiction. Historically, GABA neurochemistry in humans has been difficult to study due to methodological limitations. In recent years, proton magnetic resonance spectroscopy (1H-MRS, MRS) has emerged as a non-invasive imaging technique that can detect and quantify human brain metabolites in vivo. Novel sequencing and spectral editing methods have since been developed to allow for quantification of GABA. This review outlines the clinical research utilization of 1H-MRS in understanding GABA neurochemistry in addiction and summarizes current literature that reports GABA measurements by MRS in addiction. Research on alcohol, nicotine, cocaine, and cannabis addiction all suggest medications that modulate GABA signaling may be effective in reducing withdrawal, craving, and other addictive behaviors. Thus, we discuss how improvements in current MRS techniques and design can optimize GABA quantification in future studies and explore how monitoring changes to brain GABA could help identify risk factors, improve treatment efficacy, further characterize the nature of addiction, and provide crucial insights for future pharmacological development. Full article
(This article belongs to the Special Issue GABA Signaling: Therapeutic Targets for Neurodegenerative and Neurodevelopmental Disorders)
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20 pages, 1376 KiB  
Review
Targeting the Cation-Chloride Co-Transporter NKCC1 to Re-Establish GABAergic Inhibition and an Appropriate Excitatory/Inhibitory Balance in Selective Neuronal Circuits: A Novel Approach for the Treatment of Alzheimer’s Disease
by Simona Capsoni, Ivan Arisi, Francesca Malerba, Mara D’Onofrio, Antonino Cattaneo and Enrico Cherubini
Brain Sci. 2022, 12(6), 783; https://doi.org/10.3390/brainsci12060783 - 15 Jun 2022
Cited by 4 | Viewed by 3183
Abstract
GABA, the main inhibitory neurotransmitter in the adult brain, depolarizes and excites immature neurons because of an initially higher intracellular chloride concentration [Cl−]i due to the delayed expression of the chloride exporter KCC2 at birth. Depolarization-induced calcium rise via NMDA receptors [...] Read more.
GABA, the main inhibitory neurotransmitter in the adult brain, depolarizes and excites immature neurons because of an initially higher intracellular chloride concentration [Cl−]i due to the delayed expression of the chloride exporter KCC2 at birth. Depolarization-induced calcium rise via NMDA receptors and voltage-dependent calcium channels is instrumental in shaping neuronal circuits and in controlling the excitatory (E)/inhibitory (I) balance in selective brain areas. An E/I imbalance accounts for cognitive impairment observed in several neuropsychiatric disorders. The aim of this review is to summarize recent data on the mechanisms by which alterations of GABAergic signaling alter the E/I balance in cortical and hippocampal neurons in Alzheimer’s disease (AD) and the role of cation-chloride co-transporters in this process. In particular, we discuss the NGF and AD relationship and how mice engineered to express recombinant neutralizing anti-NGF antibodies (AD11 mice), which develop a neurodegenerative pathology reminiscent of that observed in AD patients, exhibit a depolarizing action of GABA due to KCC2 impairment. Treating AD and other forms of dementia with bumetanide, a selective NKCC1 antagonist, contributes to re-establishing a proper E/I balance in selective brain areas, leading to amelioration of AD symptoms and the slowing down of disease progression. Full article
(This article belongs to the Special Issue GABA Signaling: Therapeutic Targets for Neurodegenerative and Neurodevelopmental Disorders)
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14 pages, 764 KiB  
Review
NKCC1 Deficiency in Forming Hippocampal Circuits Triggers Neurodevelopmental Disorder: Role of BDNF-TrkB Signalling
by Jacek Szymanski and Liliana Minichiello
Brain Sci. 2022, 12(4), 502; https://doi.org/10.3390/brainsci12040502 - 15 Apr 2022
Cited by 5 | Viewed by 2638
Abstract
The time-sensitive GABA shift from excitatory to inhibitory is critical in early neural circuits development and depends upon developmentally regulated expression of cation-chloride cotransporters NKCC1 and KCC2. NKCC1, encoded by the SLC12A2 gene, regulates neuronal Cl− homeostasis by chloride import working opposite [...] Read more.
The time-sensitive GABA shift from excitatory to inhibitory is critical in early neural circuits development and depends upon developmentally regulated expression of cation-chloride cotransporters NKCC1 and KCC2. NKCC1, encoded by the SLC12A2 gene, regulates neuronal Cl− homeostasis by chloride import working opposite KCC2. The high NKCC1/KCC2 expression ratio decreases in early neural development contributing to GABA shift. Human SLC12A2 loss-of-function mutations were recently associated with a multisystem disorder affecting neural development. However, the multisystem phenotype of rodent Nkcc1 knockout models makes neurodevelopment challenging to study. Brain-Derived Neurotrophic Factor (BDNF)-NTRK2/TrkB signalling controls KCC2 expression during neural development, but its impact on NKCC1 is still controversial. Here, we discuss recent evidence supporting BDNF-TrkB signalling controlling Nkcc1 expression and the GABA shift during hippocampal circuit formation. Namely, specific deletion of Ntrk2/Trkb from immature mouse hippocampal dentate granule cells (DGCs) affects their integration and maturation in the hippocampal circuitry and reduces Nkcc1 expression in their target region, the CA3 principal cells, leading to premature GABA shift, ultimately influencing the establishment of functional hippocampal circuitry and animal behaviour in adulthood. Thus, immature DGCs emerge as a potential therapeutic target as GABAergic transmission is vital for specific neural progenitors generating dentate neurogenesis in early development and the mature brain. Full article
(This article belongs to the Special Issue GABA Signaling: Therapeutic Targets for Neurodegenerative and Neurodevelopmental Disorders)
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21 pages, 1171 KiB  
Review
Keeping the Balance: GABAB Receptors in the Developing Brain and Beyond
by Davide Bassetti
Brain Sci. 2022, 12(4), 419; https://doi.org/10.3390/brainsci12040419 - 22 Mar 2022
Cited by 14 | Viewed by 5846
Abstract
The main neurotransmitter in the brain responsible for the inhibition of neuronal activity is γ-aminobutyric acid (GABA). It plays a crucial role in circuit formation during development, both via its primary effects as a neurotransmitter and also as a trophic factor. The GABA [...] Read more.
The main neurotransmitter in the brain responsible for the inhibition of neuronal activity is γ-aminobutyric acid (GABA). It plays a crucial role in circuit formation during development, both via its primary effects as a neurotransmitter and also as a trophic factor. The GABAB receptors (GABABRs) are G protein-coupled metabotropic receptors; on one hand, they can influence proliferation and migration; and, on the other, they can inhibit cells by modulating the function of K+ and Ca2+ channels, doing so on a slower time scale and with a longer-lasting effect compared to ionotropic GABAA receptors. GABABRs are expressed pre- and post-synaptically, at both glutamatergic and GABAergic terminals, thus being able to shape neuronal activity, plasticity, and the balance between excitatory and inhibitory synaptic transmission in response to varying levels of extracellular GABA concentration. Furthermore, given their subunit composition and their ability to form complexes with several associated proteins, GABABRs display heterogeneity with regard to their function, which makes them a promising target for pharmacological interventions. This review will describe (i) the latest results concerning GABABRs/GABABR-complex structures, their function, and the developmental time course of their appearance and functional integration in the brain, (ii) their involvement in manifestation of various pathophysiological conditions, and (iii) the current status of preclinical and clinical studies involving GABABR-targeting drugs. Full article
(This article belongs to the Special Issue GABA Signaling: Therapeutic Targets for Neurodegenerative and Neurodevelopmental Disorders)
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