Modulators of GABAA receptor-mediated inhibition in the treatment of neuropsychiatric disorders: past, present, and future

Thompson, Scott M.

doi:10.1038/s41386-023-01728-8

Cited by 19 publications

(9 citation statements)

References 181 publications

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“…Additionally, behavioral studies beyond those performed (Lambert et al, 2024) should investigate the cognitive and behavioral consequences of selectively manipulating these receptors in PV interneurons to further elucidate their functional relevance. These extensions of the present work will be important to rational development of drugs that target δ-containing GABAA receptors, of current interest neurospsychiatry (Whissell et al, 2015;Maguire and Mennerick, 2023;Thompson, 2024).…”

Section: Discussionmentioning

confidence: 84%

“…Dysregulation of PV interneuron function and disruption of mPFC network dynamics have been implicated in various neuropsychiatric disorders, including schizophrenia and autism spectrum disorders (Xu et al, 2019). Our results provide insights into the specific contribution of δ-containing GABAA receptors in shaping the excitability and inhibitory output of PV interneurons in mPFC, offering potential avenues for therapeutic interventions targeting these receptors or the associated signaling pathways (Thompson, 2024).…”

Section: Discussionmentioning

confidence: 90%

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δ-containing GABA_Areceptors on parvalbumin interneurons modulate neuronal excitability and network dynamics in the mouse medial prefrontal cortex

Lu,

Shu,

Lambert

et al. 2024

Preprint

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In medial prefrontal cortex (mPFC), fast-spiking parvalbumin (PV) interneurons regulate excitability and microcircuit oscillatory activity important for cognition. Although PV interneurons inhibit pyramidal neurons, they themselves express δ subunits of GABAA receptors important for slow inhibition. However, the specific contribution of δ-containing GABAA receptors to the function of PV interneurons in mPFC is unclear. We explored cellular, synaptic, and local-circuit activity in PV interneurons and pyramidal neurons in mouse mPFC after selectively deleting δ subunits in PV interneurons (cKO mice). In current-clamp recordings, cKO PV interneurons exhibited a higher frequency of action potentials and higher input resistance than wild type (WT) PV interneurons. Picrotoxin increased firing and GABA decreased firing in WT PV interneurons but not in cKO PV interneurons. The δ-preferring agonist THIP reduced spontaneous inhibitory postsynaptic currents in WT pyramidal neurons but not in cKO pyramidal neurons. In WT slices, depolarizing the network with 400 nM kainate increased firing of pyramidal neurons but had little effect on PV interneuron firing. By contrast, in cKO slices kainate recruited PV interneurons at the expense of pyramidal neurons. At the population level, kainate induced broadband increases in local field potentials in WT but not cKO slices. These results on cells and the network can be understood through increased excitability of cKO PV interneurons. In summary, our study demonstrates that δ-containing GABAA receptors in mPFC PV interneurons play a crucial role in regulating their excitability and the phasic inhibition of pyramidal neurons, elucidating intricate mechanisms governing cortical circuitry.Significance statementBy selectively deleting δ-containing GABAA receptors in PV interneurons, we demonstrate the importance of these receptors on PV interneuron excitability, synaptic inhibition of pyramidal neurons, and circuit function.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 90%

δ-containing GABA_Areceptors on parvalbumin interneurons modulate neuronal excitability and network dynamics in the mouse medial prefrontal cortex

Lu,

Shu,

Lambert

et al. 2024

Preprint

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“…Recent approval by the Food and Drug Administration of the use of allopregnanolone (brexanolone) to treat post-partum depression has rekindled enthusiasm for exploring their potential as new medicines. The development of subtype-selective modulators of GABA A receptors for the treatment of neuropsychiatric disorders is progressing well, with more than 20 possible therapeutic agents in commercial development (Thompson, 2023). These agents mainly target receptors containing α2/3, α5, and δ subunits.…”

Section: Neurosteroidsmentioning

confidence: 99%

Milestone review: GABA, from chemistry, conformations, ionotropic receptors, modulators, epilepsy, flavonoids, and stress to neuro‐nutraceuticals

Johnston,

Beart

2024

Journal of Neurochemistry

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Arising out of a PhD project more than 50 years ago to synthesise analogues of the neurotransmitter GABA, a series of new chemical entities were found to have selective actions on ionotropic GABA receptors. Several of these neurochemicals are now commercially available. A new subtype of these receptors was discovered that could be a target for the treatment of myopia, the facilitation of learning and memory, and the improvement of post‐stroke motor recovery. The development of these new chemical entities over many years demonstrates the importance of neurochemicals with which to investigate selective aspects of GABA receptors and illustrates the significance of collaboration between chemists and biologists in neurochemistry. Vital were the improvements in synthetic organic chemistry and the use of functional human receptors expressed in oocytes. Current interest in ionotropic GABA receptors includes the clinical development of subtype‐specific agents and the role of gain‐of‐function receptor variants in epilepsy. Dietary flavonoids were found to cross the blood–brain barrier to influence brain function. Natural and synthetic flavonoids had a range of effects on GABA receptors, ranging from positive, silent, and negative allosteric modulators, to even second‐order modulation of first‐order modulators. Flavonoids have been called “a new family of benzodiazepines.” Like benzodiazepines, flavonoids reduce stress. Stress produces changes in GABA receptors in the brain that may be because of changes in endogenous modulators, such as neurosteroids and corticosteroids. GABA also occurs naturally in the diet leading to studies of the effects of oral GABA on brain function. This finding has resulted in studies of GABA and related neurochemicals as neuro‐nutraceuticals. GABA systems in the gut microbiome are essential to such studies. The actions of oral GABA and of GABA‐enriched beverages and foodstuffs are now an area of considerable scientific and commercial interest. GABA is a deceptively simple chemical that can take up many shapes, which may underlie its complex functions. The need for new chemical entities with selective actions for further studies highlights the need for continuing collaboration between chemists and biologists.

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“…The GABA A receptors are membrane proteins belonging to the superfamily of Cysloop ligand-gated ion channels that include serotonin (5-HT 3 ), GABA C , nicotinic acetylcholine, and glycine receptors [27,28]. They are pentameric structures composed by the combination of different subunits (α1-α6, β1-β3, γ1-γ3, δ, ϱ1-ϱ3, ε, θ, and π) conferring different physiological, pharmacological, and biophysical properties [28][29][30]. These GABA receptors are located at the synapse (containing α1-α3 and γ subunits) and extrasynaptic regions (containing α4-α6 and δ subunits), mediating phasic and tonic inhibition, respectively [27][28][29].…”

Section: Introductionmentioning

confidence: 99%

Regulation of Hippocampal GABAergic Transmission by Fluoxetine and Its Metabolite Norfluoxetine

Vázquez-Gómez,

Hernández-Abrego,

Mejía-Piedras

et al. 2024

Receptors

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Major depression is related to dysfunction of the GABAergic pathway. Interestingly, the antidepressant fluoxetine modifies GABAergic neurotransmission in human and animal models of depression. However, the effects of norfluoxetine (the main metabolite of fluoxetine) on GABAergic neurotransmission have not yet been studied. Therefore, we explored whether fluoxetine and/or norfluoxetine may regulate GABAergic transmission and whether these substances interact with GABAA receptors in hippocampal CA1 stratum radiatum interneurons. For these purposes, we recorded the firing profile, GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs), and currents induced by GABA puffs in stratum radiatum interneurons using both whole-cell current- and voltage-clamp techniques. Interneurons were selected according with their high firing profile. We found that both fluoxetine and norfluoxetine (at 20 µM) significantly decreased the frequency of sIPSCs without modifying their amplitude and decreased the amplitude of GABA-induced currents. These results indicate that fluoxetine and norfluoxetine decrease GABA release from neurons contacting stratum radiatum interneurons and negatively modulate GABAA receptors in these interneurons, resulting in their disinhibition, which in turn may contribute to increasing the inhibition of hippocampal CA1 pyramidal neurons.

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Modulators of GABAA receptor-mediated inhibition in the treatment of neuropsychiatric disorders: past, present, and future

Cited by 19 publications

References 181 publications

δ-containing GABA_Areceptors on parvalbumin interneurons modulate neuronal excitability and network dynamics in the mouse medial prefrontal cortex

δ-containing GABA_Areceptors on parvalbumin interneurons modulate neuronal excitability and network dynamics in the mouse medial prefrontal cortex

Milestone review: GABA, from chemistry, conformations, ionotropic receptors, modulators, epilepsy, flavonoids, and stress to neuro‐nutraceuticals

Regulation of Hippocampal GABAergic Transmission by Fluoxetine and Its Metabolite Norfluoxetine

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Modulators of GABAA receptor-mediated inhibition in the treatment of neuropsychiatric disorders: past, present, and future

Cited by 19 publications

References 181 publications

δ-containing GABAAreceptors on parvalbumin interneurons modulate neuronal excitability and network dynamics in the mouse medial prefrontal cortex

δ-containing GABAAreceptors on parvalbumin interneurons modulate neuronal excitability and network dynamics in the mouse medial prefrontal cortex

Milestone review: GABA, from chemistry, conformations, ionotropic receptors, modulators, epilepsy, flavonoids, and stress to neuro‐nutraceuticals

Regulation of Hippocampal GABAergic Transmission by Fluoxetine and Its Metabolite Norfluoxetine

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Product

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δ-containing GABA_Areceptors on parvalbumin interneurons modulate neuronal excitability and network dynamics in the mouse medial prefrontal cortex

δ-containing GABA_Areceptors on parvalbumin interneurons modulate neuronal excitability and network dynamics in the mouse medial prefrontal cortex