Sustained treatment with an α5 GABA A receptor negative allosteric modulator delays excitatory circuit development while maintaining GABAergic neurotransmission

Nuwer, Jessica L.; Brady, Megan L.; Povysheva, Nadezhda V.; Coyne, Amanda; Jacob, Tija C.

doi:10.1016/j.neuropharm.2021.108724

Cited by 4 publications

(1 citation statement)

References 87 publications

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“…While potentiating inhibition blocks eLTP, stifling inhibition with the GABA A R NAM DMCM ( Seabrook et al, 1997 ) or the competitive antagonist bicuculline ( Matsuyama et al, 2008 ) potentiates eLTP, which is associated with specific alterations in NMDAR expression. In immature DIV14 hippocampal neurons, 48-h inhibition of α5-GABA A Rs with the NAM L-655,708 decreased GluN2A, but increased synaptic GluN2B ( Nuwer et al, 2021 ). Interestingly, as neurons mature to DIV21, L-655,708 had the opposite effect—synaptic GluN2A increased while synaptic GluN2B decreased.…”

Section: Interplay Between Glutamatergic and Gabaergic Synapsesmentioning

confidence: 99%

The Yin and Yang of GABAergic and Glutamatergic Synaptic Plasticity: Opposites in Balance by Crosstalking Mechanisms

Chapman

Nuwer

Jacob

2022

Front. Synaptic Neurosci.

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Synaptic plasticity is a critical process that regulates neuronal activity by allowing neurons to adjust their synaptic strength in response to changes in activity. Despite the high proximity of excitatory glutamatergic and inhibitory GABAergic postsynaptic zones and their functional integration within dendritic regions, concurrent plasticity has historically been underassessed. Growing evidence for pathological disruptions in the excitation and inhibition (E/I) balance in neurological and neurodevelopmental disorders indicates the need for an improved, more “holistic” understanding of synaptic interplay. There continues to be a long-standing focus on the persistent strengthening of excitation (excitatory long-term potentiation; eLTP) and its role in learning and memory, although the importance of inhibitory long-term potentiation (iLTP) and depression (iLTD) has become increasingly apparent. Emerging evidence further points to a dynamic dialogue between excitatory and inhibitory synapses, but much remains to be understood regarding the mechanisms and extent of this exchange. In this mini-review, we explore the role calcium signaling and synaptic crosstalk play in regulating postsynaptic plasticity and neuronal excitability. We examine current knowledge on GABAergic and glutamatergic synapse responses to perturbances in activity, with a focus on postsynaptic plasticity induced by short-term pharmacological treatments which act to either enhance or reduce neuronal excitability via ionotropic receptor regulation in neuronal culture. To delve deeper into potential mechanisms of synaptic crosstalk, we discuss the influence of synaptic activity on key regulatory proteins, including kinases, phosphatases, and synaptic structural/scaffolding proteins. Finally, we briefly suggest avenues for future research to better understand the crosstalk between glutamatergic and GABAergic synapses.

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Section: Interplay Between Glutamatergic and Gabaergic Synapsesmentioning

confidence: 99%

The Yin and Yang of GABAergic and Glutamatergic Synaptic Plasticity: Opposites in Balance by Crosstalking Mechanisms

Chapman

Nuwer

Jacob

2022

Front. Synaptic Neurosci.

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Long-term α5 GABA A receptor negative allosteric modulator treatment reduces NMDAR-mediated neuronal excitation and maintains basal neuronal inhibition

2023

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γ-Aminobutyric acid transporter and GABAA receptor mechanisms in Slc6a1+/A288V and Slc6a1+/S295L mice associated with developmental and epileptic encephalopathies

Shen,

Nwosu,

Honer

et al. 2024

Brain Communications

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We have previously characterized the molecular mechanisms for variants in γ-aminobutyric acid transporter 1-encoding solute carrier family 6-member 1 (SLC6A1) in vitro and concluded that a partial or complete loss of γ-aminobutyric acid uptake due to impaired protein trafficking is the primary aetiology. Impairment of γ-aminobutyric acid transporter 1 function could cause compensatory changes in the expression of γ-aminobutyric acid receptors, which, in turn, modify disease pathophysiology and phenotype. Here we used different approaches including radioactive 3H γ-aminobutyric acid uptake in cells and synaptosomes, immunohistochemistry and confocal microscopy as well as brain slice surface protein biotinylation to characterize Slc6a1+/A288V and Slc6a1+/S295L mice, representative of a partial or a complete loss of function of SLC6A1 mutations, respectively. We employed the γ-aminobutyric acid transporter 1-specific inhibitor [3H]tiagabine binding and GABAA receptor subunit-specific radioligand binding to profile the γ-aminobutyric acid transporter 1 and GABAA receptor expression in major brain regions such as cortex, cerebellum, hippocampus and thalamus. We also determined the total and surface expression of γ-aminobutyric acid transporter 1, γ-aminobutyric acid transporter 3 and expression of GABAA receptor in the major brain regions in the knockin mice. We found that γ-aminobutyric acid transporter 1 protein was markedly reduced in cortex, hippocampus, thalamus and cerebellum in both mutant mouse lines. Consistent with the findings of reduced γ-aminobutyric acid uptake for both γ-aminobutyric acid transporter 1(A288V) and γ-aminobutyric acid transporter 1(S295L), both the total and the γ-aminobutyric acid transporter 1-mediated 3H γ-aminobutyric acid reuptake was reduced. We found that γ-aminobutyric acid transporter 3 is only abundantly expressed in the thalamus and there was no compensatory increase of γ-aminobutyric acid transporter 3 in either of the mutant mouse lines. γ-Aminobutyric acid transporter 1 was reduced in both somatic regions and nonsomatic regions in both mouse models, in which a ring-like structure was identified only in the Slc6a1+/A288V mouse, suggesting more γ-aminobutyric acid transporter 1 retention inside endoplasmic reticulum in the Slc6a1+/A288V mouse. The [3H]tiagabine binding was similar in both mouse models despite the difference in γ-aminobutyric acid uptake function and γ-aminobutyric acid transporter 1 protein expression for both mutations. There were no differences in GABAA receptor subtype expression, except for a small increase in the expression of α5 subunits of GABAA receptor in the hippocampus of Slc6a1S295L homozygous mice, suggesting a potential interaction between the expression of this GABAA receptor subtype and the mutant γ-aminobutyric acid transporter 1. The study provides the first comprehensive characterization of the SLC6A1 mutations in vivo in two representative mouse models. Because both γ-aminobutyric acid transporter 1 and GABAA receptors are targets for anti-seizure medications, the findings from this study can help guide tailored treatment options based on the expression and function of γ-aminobutyric acid transporter 1 and GABAA receptor in SLC6A1 mutation-mediated neurodevelopmental and epileptic encephalopathies.

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Sustained treatment with an α5 GABA A receptor negative allosteric modulator delays excitatory circuit development while maintaining GABAergic neurotransmission

Cited by 4 publications

References 87 publications

The Yin and Yang of GABAergic and Glutamatergic Synaptic Plasticity: Opposites in Balance by Crosstalking Mechanisms

The Yin and Yang of GABAergic and Glutamatergic Synaptic Plasticity: Opposites in Balance by Crosstalking Mechanisms

Long-term α5 GABA A receptor negative allosteric modulator treatment reduces NMDAR-mediated neuronal excitation and maintains basal neuronal inhibition

γ-Aminobutyric acid transporter and GABAA receptor mechanisms in Slc6a1+/A288V and Slc6a1+/S295L mice associated with developmental and epileptic encephalopathies

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