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GABA Signaling in Health and Disease in the Nervous System

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (30 March 2024) | Viewed by 8146

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Dr. Alexandre Hiroaki Kihara

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Centro de Matemática, Computação e Cognição, Universidade Federal do ABC, São Bernardo do Campo, Brazil
Interests: stem cells; sci; genome; CRISPR associated endonuclease Cas9; gene editing; electrocorticography; high frequency oscillation; seizures
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Prof. Dr. Afia B. Ali

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UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK
Interests: electrophysiology, neuropharmacology and histopathology of local circuit excitatory and inhibitory neurons in cortical regions; focusing on the glutamate and GABAA receptors and transporters

Special Issue Information

Dear Colleagues,

Gabaergic signaling is essential in the brain throughout development, adulthood, and aging. Indeed, gamma-aminobutyric acid (GABA) is involved in processes, such as proliferation, migration, and differentiation of neural progenitor cells, during neurodevelopment. Moreover, GABA was shown to control neuritogenesis and maturation of synapses. In the mature brain, GABA is considered the main inhibitory neurotransmitter, contributing to the excitatory/inhibitory balance. In fact, changes in this balance are often related to neuronal disorders and aging-related neurodegenerative diseases. Moreover, recent reports described hippocampal inhibitory neurons playing unsuspected roles, such as coding space and speed. Considering all this information, authors are invited to contribute to this relevant topic in neuroscience.

Dr. Alexandre Hiroaki Kihara
Prof. Dr. Afia B. Ali
Guest Editors

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Keywords

gamma-aminobutyric acid
neurodevelopment
neuronal differentiation
neuronal disorders
neurodegenerative diseases

Published Papers (7 papers)

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23 pages, 11944 KiB

Open AccessArticle

Oxytocin Modifies the Excitability and the Action Potential Shape of the Hippocampal CA1 GABAergic Interneurons

by Antonio Nicolas Castagno, Paolo Spaiardi, Arianna Trucco, Claudia Maniezzi, Francesca Raffin, Maria Mancini, Alessandro Nicois, Jessica Cazzola, Matilda Pedrinazzi, Paola Del Papa, Antonio Pisani, Francesca Talpo and Gerardo Rosario Biella

Int. J. Mol. Sci. 2024, 25(5), 2613; https://doi.org/10.3390/ijms25052613 - 23 Feb 2024

Viewed by 718

Abstract

Oxytocin (OT) is a neuropeptide that modulates social-related behavior and cognition in the central nervous system of mammals. In the CA1 area of the hippocampus, the indirect effects of the OT on the pyramidal neurons and their role in information processing have been elucidated. However, limited data are available concerning the direct modulation exerted by OT on the CA1 interneurons (INs) expressing the oxytocin receptor (OTR). Here, we demonstrated that TGOT (Thr4,Gly7-oxytocin), a selective OTR agonist, affects not only the membrane potential and the firing frequency but also the neuronal excitability and the shape of the action potentials (APs) of these INs in mice. Furthermore, we constructed linear mixed-effects models (LMMs) to unravel the dependencies between the AP parameters and the firing frequency, also considering how TGOT can interact with them to strengthen or weaken these influences. Our analyses indicate that OT regulates the functionality of the CA1 GABAergic INs through different and independent mechanisms. Specifically, the increase in neuronal firing rate can be attributed to the depolarizing effect on the membrane potential and the related enhancement in cellular excitability by the peptide. In contrast, the significant changes in the AP shape are directly linked to oxytocinergic modulation. Importantly, these alterations in AP shape are not associated with the TGOT-induced increase in neuronal firing rate, being themselves critical for signal processing. Full article

(This article belongs to the Special Issue GABA Signaling in Health and Disease in the Nervous System)

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23 pages, 4964 KiB

Open AccessArticle

Serotonergic Modulation of the Excitation/Inhibition Balance in the Visual Cortex

by Estevão Carlos-Lima, Guilherme Shigueto Vilar Higa, Felipe José Costa Viana, Alicia Moraes Tamais, Emily Cruvinel, Fernando da Silva Borges, José Francis-Oliveira, Henning Ulrich and Roberto De Pasquale

Int. J. Mol. Sci. 2024, 25(1), 519; https://doi.org/10.3390/ijms25010519 - 30 Dec 2023

Cited by 1 | Viewed by 796

Abstract

Serotonergic neurons constitute one of the main systems of neuromodulators, whose diffuse projections regulate the functions of the cerebral cortex. Serotonin (5-HT) is known to play a crucial role in the differential modulation of cortical activity related to behavioral contexts. Some features of the 5-HT signaling organization suggest its possible participation as a modulator of activity-dependent synaptic changes during the critical period of the primary visual cortex (V1). Cells of the serotonergic system are among the first neurons to differentiate and operate. During postnatal development, ramifications from raphe nuclei become massively distributed in the visual cortical area, remarkably increasing the availability of 5-HT for the regulation of excitatory and inhibitory synaptic activity. A substantial amount of evidence has demonstrated that synaptic plasticity at pyramidal neurons of the superficial layers of V1 critically depends on a fine regulation of the balance between excitation and inhibition (E/I). 5-HT could therefore play an important role in controlling this balance, providing the appropriate excitability conditions that favor synaptic modifications. In order to explore this possibility, the present work used in vitro intracellular electrophysiological recording techniques to study the effects of 5-HT on the E/I balance of V1 layer 2/3 neurons, during the critical period. Serotonergic action on the E/I balance has been analyzed on spontaneous activity, evoked synaptic responses, and long-term depression (LTD). Our results pointed out that the predominant action of 5-HT implies a reduction in the E/I balance. 5-HT promoted LTD at excitatory synapses while blocking it at inhibitory synaptic sites, thus shifting the Hebbian alterations of synaptic strength towards lower levels of E/I balance. Full article

(This article belongs to the Special Issue GABA Signaling in Health and Disease in the Nervous System)

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18 pages, 3027 KiB

Open AccessArticle

Age-Dependent Sex Differences in Perineuronal Nets in an APP Mouse Model of Alzheimer’s Disease Are Brain Region-Specific

by Rayane Rahmani, Naiomi Rambarack, Jaijeet Singh, Andrew Constanti and Afia B. Ali

Int. J. Mol. Sci. 2023, 24(19), 14917; https://doi.org/10.3390/ijms241914917 - 05 Oct 2023

Cited by 2 | Viewed by 2269

Abstract

Alzheimer’s disease (AD) is the most common form of dementia, which disproportionately affects women. AD symptoms include progressive memory loss associated with amyloid-β (Aβ) plaques and dismantled synaptic mechanisms. Perineuronal nets (PNNs) are important components of the extracellular matrix with a critical role in synaptic stabilisation and have been shown to be influenced by microglia, which enter an activated state during AD. This study aimed to investigate whether sex differences affected the density of PNNs alongside the labelling of microglia and Aβ plaques density.We performed neurochemistry experiments using acute brain slices from both sexes of the APP^NL-F/NL-F mouse model of AD, aged-matched (2–5 and 12–16 months) to wild-type mice, combined with a weighted gene co-expression network analysis (WGCNA). The lateral entorhinal cortex (LEC) and hippocampal CA1, which are vulnerable during early AD pathology, were investigated and compared to the presubiculum (PRS), a region unscathed by AD pathology. The highest density of PNNs was found in the LEC and PRS regions of aged APP^NL-F/NL-F mice with a region-specific sex differences. Analysis of the CA1 region using multiplex-fluorescent images from aged APP^NL-F/NL-F mice showed regions of dense Aβ plaques near clusters of CD68, indicative of activated microglia and PNNs. This was consistent with the results of WGCNA performed on normalised data on microglial cells isolated from age-matched, late-stage male and female wild-type and APP knock-in mice, which revealed one microglial module that showed differential expression associated with tissue, age, genotype, and sex, which showed enrichment for fc-receptor-mediated phagocytosis. Our data are consistent with the hypothesis that sex-related differences contribute to a disrupted interaction between PNNs and microglia in specific brain regions associated with AD pathogenesis. Full article

(This article belongs to the Special Issue GABA Signaling in Health and Disease in the Nervous System)

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21 pages, 7915 KiB

Open AccessArticle

Impact of Developmental Changes of GABA_A Receptors on Interneuron-NG2 Glia Transmission in the Hippocampus

by Linda Patt, Dario Tascio, Catia Domingos, Aline Timmermann, Ronald Jabs, Christian Henneberger, Christian Steinhäuser and Gerald Seifert

Int. J. Mol. Sci. 2023, 24(17), 13490; https://doi.org/10.3390/ijms241713490 - 30 Aug 2023

Cited by 2 | Viewed by 1020

Abstract

NG2 glia receive synaptic input from neurons, but the functional impact of this glial innervation is not well understood. In the developing cerebellum and somatosensory cortex the GABAergic input might regulate NG2 glia differentiation and myelination, and a switch from synaptic to extrasynaptic neuron–glia signaling was reported in the latter region. Myelination in the hippocampus is sparse, and most NG2 glia retain their phenotype throughout adulthood, raising the question of the properties and function of neuron-NG2 glia synapses in that brain region. Here, we compared spontaneous and evoked GABA_A receptor-mediated currents of NG2 glia in juvenile and adult hippocampi of mice of either sex and assessed the mode of interneuron–glial signaling changes during development. With patch-clamp and pharmacological analyses, we found a decrease in innervation of hippocampal NG2 glia between postnatal days 10 and 60. At the adult stage, enhanced activation of extrasynaptic receptors occurred, indicating a spillover of GABA. This switch from synaptic to extrasynaptic receptor activation was accompanied by downregulation of γ2 and upregulation of the α5 subunit. Molecular analyses and high-resolution expansion microscopy revealed mechanisms of glial GABA_A receptor trafficking and clustering. We found that gephyrin and radixin are organized in separate clusters along glial processes. Surprisingly, the developmental loss of γ2 and postsynaptic receptors were not accompanied by altered glial expression of scaffolding proteins, auxiliary receptor subunits or postsynaptic interaction proteins. The GABAergic input to NG2 glia might contribute to the release of neurotrophic factors from these cells and influence neuronal synaptic plasticity. Full article

(This article belongs to the Special Issue GABA Signaling in Health and Disease in the Nervous System)

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20 pages, 9119 KiB

Open AccessArticle

ERK1/2-Dependent Phosphorylation of GABA_B1(S867/T872), Controlled by CaMKIIβ, Is Required for GABA_B Receptor Degradation under Physiological and Pathological Conditions

by Musadiq A. Bhat, Thomas Grampp and Dietmar Benke

Int. J. Mol. Sci. 2023, 24(17), 13436; https://doi.org/10.3390/ijms241713436 - 30 Aug 2023

Cited by 1 | Viewed by 820

Abstract

GABA_B receptor-mediated inhibition is indispensable for maintaining a healthy neuronal excitation/inhibition balance. Many neurological diseases are associated with a disturbed excitation/inhibition balance and downregulation of GABA_B receptors due to enhanced sorting of the receptors to lysosomal degradation. A key event triggering the downregulation of the receptors is the phosphorylation of S867 in the GABA_B1 subunit mediated by CaMKIIβ. Interestingly, close to S867 in GABA_B1 exists another phosphorylation site, T872. Therefore, the question arose as to whether phosphorylation of T872 is involved in downregulating the receptors and whether phosphorylation of this site is also mediated by CaMKIIβ or by another protein kinase. Here, we show that mutational inactivation of T872 in GABA_B1 prevented the degradation of the receptors in cultured neurons. We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABA_B receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABA_B1. Blocking ERK activity after subjecting neurons to ischemic stress completely restored downregulated GABA_B receptor expression to normal levels. Thus, preventing ERK1/2-mediated phosphorylation of S867/T872 in GABA_B1 is an opportunity to inhibit the pathological downregulation of the receptors after ischemic stress and is expected to restore a healthy neuronal excitation/inhibition balance. Full article

(This article belongs to the Special Issue GABA Signaling in Health and Disease in the Nervous System)

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12 pages, 1326 KiB

Open AccessCommunication

GL-II-73, a Positive Allosteric Modulator of α5GABA_A Receptors, Reverses Dopamine System Dysfunction Associated with Pilocarpine-Induced Temporal Lobe Epilepsy

by Alexandra M. McCoy, Thomas D. Prevot, Dishary Sharmin, James M. Cook, Etienne L. Sibille and Daniel J. Lodge

Int. J. Mol. Sci. 2023, 24(14), 11588; https://doi.org/10.3390/ijms241411588 - 18 Jul 2023

Cited by 1 | Viewed by 1191

Abstract

Although seizures are a hallmark feature of temporal lobe epilepsy (TLE), psychiatric comorbidities, including psychosis, are frequently associated with TLE and contribute to decreased quality of life. Currently, there are no defined therapeutic protocols to manage psychosis in TLE patients, as antipsychotic agents may induce epileptic seizures and are associated with severe side effects and pharmacokinetic and pharmacodynamic interactions with antiepileptic drugs. Thus, novel treatment strategies are necessary. Several lines of evidence suggest that hippocampal hyperactivity is central to the pathology of both TLE and psychosis; therefore, restoring hippocampal activity back to normal levels may be a novel therapeutic approach for treating psychosis in TLE. In rodent models, increased activity in the ventral hippocampus (vHipp) results in aberrant dopamine system function, which is thought to underlie symptoms of psychosis. Indeed, we have previously demonstrated that targeting α5-containing γ-aminobutyric acid receptors (α5GABA_ARs), an inhibitory receptor abundant in the hippocampus, with positive allosteric modulators (PAMs), can restore dopamine system function in rodent models displaying hippocampal hyperactivity. Thus, we posited that α5-PAMs may be beneficial in a model used to study TLE. Here, we demonstrate that pilocarpine-induced TLE is associated with increased VTA dopamine neuron activity, an effect that was completely reversed by intra-vHipp administration of GL-II-73, a selective α5-PAM. Further, pilocarpine did not alter the hippocampal α5GABA_AR expression or synaptic localization that may affect the efficacy of α5-PAMs. Taken together, these results suggest augmenting α5GABA_AR function as a novel therapeutic modality for the treatment of psychosis in TLE. Full article

(This article belongs to the Special Issue GABA Signaling in Health and Disease in the Nervous System)

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10 pages, 3239 KiB

Open AccessBrief Report

Age-Dependent Changes in the Occurrence and Segregation of GABA and Acetylcholine in the Rat Superior Cervical Ganglia

by Alfredo Hernández, Constanza González-Sierra, María Elena Zetina, Fredy Cifuentes and Miguel Angel Morales

Int. J. Mol. Sci. 2024, 25(5), 2588; https://doi.org/10.3390/ijms25052588 - 23 Feb 2024

Viewed by 453

Abstract

The occurrence, inhibitory modulation, and trophic effects of GABA have been identified in the peripheral sympathetic nervous system. We have demonstrated that GABA and acetylcholine (ACh) may colocalize in the same axonal varicosities or be segregated into separate ones in the rat superior cervical ganglia (SCG). Neurotransmitter segregation varies with age and the presence of neurotrophic factors. Here, we explored age-dependent changes in the occurrence and segregation of GABA and ACh in rats ranging from 2 weeks old (wo) to 12 months old or older. Using immunohistochemistry, we characterized the expression of L-glutamic acid decarboxylase of 67 kDa (GAD67) and vesicular acetylcholine transporter (VAChT) in the rat SCG at 2, 4, 8, 12 wo and 12 months old or older. Our findings revealed that GAD67 was greater at 2 wo compared with the other ages, whereas VAChT levels were greater at 4 wo than at 12 wo and 12 months old or older. The segregation of these neurotransmitters was more pronounced at 2 and 4 wo. We observed a caudo-rostral gradient of segregation degree at 8 and 12 wo. Data point out that the occurrence and segregation of GABA and ACh exhibit developmental adaptative changes throughout the lifetime of rats. We hypothesize that during the early postnatal period, the increase in GABA and GABA-ACh segregation promotes the release of GABA alone which might play a role in trophic actions. Full article

(This article belongs to the Special Issue GABA Signaling in Health and Disease in the Nervous System)

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