The Role of the GABAergic System in Diseases of the Central Nervous System

Zhang, Wen; Xiong, Bingrui; Zhang, Long-Qing; Huang, Xiji; Yuan, Xianglin; Tian, Yuan; Tian, Xiaojing

doi:10.1016/j.neuroscience.2021.06.037

Cited by 48 publications

(43 citation statements)

References 120 publications

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“…Our finding that the mean in vivo discharge rates were not different to controls in the presence of an accelerated intrinsic pacemaker strongly suggests a shift of the synaptic excitation-inhibition (E-I) balance towards more inhibition. Numerous studies have found altered synaptic inhibition in the dopamine-depleted basal ganglia (recently reviewed in (Zhang et al, 2021)).…”

Section: Discussionmentioning

confidence: 99%

Recovery of the fullin vivofiring range in post-lesion surviving DA SN neurons associated with Kv4.3-mediated pacemaker plasticity

Kovacheva

Shin

Farassat

et al. 2021

Preprint

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Substantia nigra dopamine (SN DA) neurons are progressively lost in Parkinson disease (PD). While the molecular and cellular mechanisms of their differential vulnerability and degeneration have been extensively studied, we still know very little about potential functional adaptations of those SN DA neurons that at least for some time manage to survive during earlier stages of PD. We utilized a partial lesion 6-OHDA mouse model to characterize initial electrophysiological impairments and chronic adaptations of surviving identified SN DA neurons, both in vivo and in vitro. Early after lesion (3 weeks), we detected a selective loss of in vivo burst firing in surviving SN DA neurons, which was accompanied by in vitro pacemaker instability. In contrast, late after lesion (>2 months), in vivo firing properties of surviving SN DA neurons had recovered in the presence of 2-fold accelerated pacemaking in vitro. Finally, we show that this chronic cell-autonomous adaptation in surviving SN DA neurons was mediated by Kv4.3 channel downregulation. Our study demonstrates substantial homeostatic plasticity of surviving SN DA neurons after a single-hit non-progressive lesion, which might contribute to the phenotype of initially surviving SN DA neurons in PD.

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Section: Discussionmentioning

confidence: 99%

Recovery of the fullin vivofiring range in post-lesion surviving DA SN neurons associated with Kv4.3-mediated pacemaker plasticity

Kovacheva

Shin

Farassat

et al. 2021

Preprint

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“…Thus, a major aim of therapeutic approaches targeting the GABA system, on which it depends for neuronal inhibition, is to recover the neuronal balance between excitation and inhibition lost in all these pathologies. Importantly, GABA is also critical in neuro-developmental disorders such as autism spectrum disorders or Angelman syndrome due to its pivotal role in the performance of central functions in the development and function of the brain such as neurogenesis, neuronal maturation and apoptosis [ 15 ]. In addition, GABA influences neural migration, acts as a neurotrophic factor, and facilitates neurite extension [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…The GABAergic system is mainly composed of GABA, GABA transporters (GATs), GABA receptors (GABA-Rs), and GABAergic neurons and neuroglia, mainly astrocytes involved in its metabolic regulation [ 15 ]. GABA neurons are widely distributed in the brain and are localized in axonic terminals, somas, and to a lesser extent in dendrites.…”

Section: Introductionmentioning

confidence: 99%

“…The first step in the GABA shunt is transamination of the α-ketoglutarate produced by the metabolism of glucose in the Krebs’ cycle by the glutamate dehydrogenase, producing L-glutamate, which must be decarboxylated by glutamic acid decarboxylases (GADs) to form GABA ( Figure 1 ). GAD includes two isoforms expressed by separate genes which have different regulatory processes and molecular properties: GAD-65, involved in synaptic transmission and plasticity, and GAD-67, which controls the metabolic GABA synthesis [ 15 ]. GAD enzymes need pyridoxine (vitamin B 6 ) as a cofactor, which is only expressed in cells using GABA as a neurotransmitter; therefore, it is used as a marker to locate GABA neurons along the CNS [ 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

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Phenolics as GABAA Receptor Ligands: An Updated Review

2022

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Natural products can act as potential GABA modulators, avoiding the undesirable effects of traditional pharmacology used for the inhibition of the central nervous system such as benzodiazepines (BZD). Phenolics, especially flavonoids and phlorotannins, have been considered as modulators of the BZD-site of GABAA receptors (GABAARs), with sedative, anxiolytic or anticonvulsant effects. However, the wide chemical structural variability of flavonoids shows their potential action at more than one additional binding site on GABAARs, which may act either negatively, positively, by neutralizing GABAARs, or directly as allosteric agonists. Therefore, the aim of the present review is to compile and discuss an update of the role of phenolics, namely as pharmacological targets involving dysfunctions of the GABA system, analyzing both their different compounds and their mechanism as GABAergic modulators. We focus this review on articles written in English since the year 2010 until the present. Of course, although more research would be necessary to fully establish the type specificity of phenolics and their pharmacological activity, the evidence supports their potential as GABAAR modulators, thereby favoring their inclusion in the development of new therapeutic targets based on natural products. Specifically, the data compiled in this review allows for the directing of future research towards ortho-dihydroxy diterpene galdosol, the flavonoids isoliquiritigenin (chalcone), rhusflavone and agathisflavone (biflavonoids), as well as the phlorotannins, dieckol and triphlorethol A. Clinically, flavonoids are the most interesting phenolics due to their potential as anticonvulsant and anxiolytic drugs, and phlorotannins are also of interest as sedative agents.

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“…However, several pathways and mechanisms are emerging that may become the basis for new drugs in the future. In recent years, accumulating evidence from various novel visualization techniques has begun to confirm the involvement of Aβ oligomers and tau protein in the loss of inhibitory neurons' plasticity [3,5,[19][20][21]23,24].…”

Section: Introductionmentioning

confidence: 99%

Digging Deeper: Advancements in Visualization of Inhibitory Synapses in Neurodegenerative Disorders

Radulović

Sunkara

Maurer

et al. 2021

IJMS

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Recent research has provided strong evidence that neurodegeneration may develop from an imbalance between synaptic structural components in the brain. Lately, inhibitory synapses communicating via the neurotransmitters GABA or glycine have come to the center of attention. Increasing evidence suggests that imbalance in the structural composition of inhibitory synapses affect deeply the ability of neurons to communicate effectively over synaptic connections. Progressive failure of synaptic plasticity and memory are thus hallmarks of neurodegenerative diseases. In order to prove that structural changes at synapses contribute to neurodegeneration, we need to visualize single-molecule interactions at synaptic sites in an exact spatial and time frame. This visualization has been restricted in terms of spatial and temporal resolution. New developments in electron microscopy and super-resolution microscopy have improved spatial and time resolution tremendously, opening up numerous possibilities. Here we critically review current and recently developed methods for high-resolution visualization of inhibitory synapses in the context of neurodegenerative diseases. We present advantages, strengths, weaknesses, and current limitations for selected methods in research, as well as present a future perspective. A range of new options has become available that will soon help understand the involvement of inhibitory synapses in neurodegenerative disorders.

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The Role of the GABAergic System in Diseases of the Central Nervous System

Cited by 48 publications

References 120 publications

Recovery of the fullin vivofiring range in post-lesion surviving DA SN neurons associated with Kv4.3-mediated pacemaker plasticity

Recovery of the fullin vivofiring range in post-lesion surviving DA SN neurons associated with Kv4.3-mediated pacemaker plasticity

Phenolics as GABAA Receptor Ligands: An Updated Review

Digging Deeper: Advancements in Visualization of Inhibitory Synapses in Neurodegenerative Disorders

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