Regulating anxiety with extrasynaptic inhibition

Botta, Paolo; Demmou, Lynda; Kasugai, Yu; Marković, Milica; Xu, Chun; Fadok, Jonathan P.; Lu, Ting-Jia; Poe, M.; Xu, Li; Cook, James M.; Rudolph, Uwe; Sah, Pankaj; Ferraguti, Francesco; Lüthi, Andreas

doi:10.1038/nn.4102

Cited by 168 publications

(194 citation statements)

References 34 publications

(72 reference statements)

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“…The study concluded that extrasynaptic α5-GABA A Rs in CEA PKCδ + neurons control anxiety. Taken together, our results and the study by Botta et al (2015) suggest the possibility that the anxiolytic-like effects of the specific modulation of α5-GABA A Rs reported here may be due, at least in part, to the positive modulation of the α5-GABA A Rs in this specific neuronal population.…”

Section: Discussionsupporting

confidence: 77%

“…As the ventral hippocampus has been linked to emotion and stress, whereas the dorsal hippocampus has been linked primarily to cognitive functions (Fanselow and Dong, 2010), α5-GABA A Rs in the ventral hippocampus may be involved in anxiolysis. Furthermore, a recent study showed that conditional genetic deletion of α5 in the central nucleus of the amygdala (CEA) leads to anxiogenic-like effects and increased fear generalization (Botta et al, 2015). The study concluded that extrasynaptic α5-GABA A Rs in CEA PKCδ + neurons control anxiety.…”

Section: Discussionmentioning

confidence: 99%

“…However, two recent studies were unable to reproduce the α3-selectivity of TP003 in recombinant receptors (Christian et al, 2015;de Lucas et al, 2015), raising the question whether the anxiolytic-like action of TP003 is really dependent on modulation of α3-GABA A Rs, and, on a broader scale, whether α3-GABA A Rs are involved at all in the modulation of anxietyrelated behaviors. Furthermore, a conditional deletion of the α5-subunit in PKCδ+ neurons in the central amygdala resulted in increased anxiety in the open-field (OF) and elevated plus maze (EPM) tests (Botta et al, 2015), suggesting a role for α5-GABA A Rs in anxiety regulation. However, it has not been examined whether systemic positive allosteric modulation of α5-GABA A Rs leads to anxiolysis.…”

Section: Introductionmentioning

confidence: 99%

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A Pharmacogenetic ‘Restriction-of-Function’ Approach Reveals Evidence for Anxiolytic-Like Actions Mediated by α5-Containing GABAA Receptors in Mice

Behlke

Foster

Liu

et al. 2016

Neuropsychopharmacol

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Benzodiazepines have been widely used for their anxiolytic actions. However, the contribution of GABA A receptor subtypes to anxiolysis is still controversial. Studies with mutant mice harboring diazepam-insensitive α-subunits α1, α2, α3, or α5 have revealed that α2-containing GABA A receptors (α2-GABA A Rs) are required for diazepam-induced anxiolysis, with no evidence for an involvement of any other α-subunit, whereas TP003, described as a selective modulator of α3-containing GABA A receptors, was shown to be anxiolytic. Here, we describe a novel, systematic approach to evaluate the role of positive allosteric modulation of each of the four diazepam-sensitive α-subtypes in anxiety-related behavioral paradigms. By combining H to R point mutations in three out of the four diazepam-sensitive α-subunits in mice with a 129X1/SvJ background, diazepam becomes a subtype-specific modulator of the remaining non-mutated α-subtype. Modulation of α5-GABA A Rs, but not of α2-GABA A Rs, increased the time in the light side of the light-dark box as well as openarm exploration in the elevated plus maze. In contrast, modulation of α3-GABA A Rs decreased open-arm exploration, whereas modulation of α2-GABA A Rs increased time in the center in the open-field test. Modulation of any single α-subtype had no effect on stress-induced hyperthermia. Our results provide evidence that modulation of α5-GABA A Rs elicits anxiolytic-like actions, whereas our data do not provide evidence for an anxiolytic-like action of α3-GABA A Rs. Thus, α5-GABA A Rs may be suitable targets for novel anxiolytic drugs.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Pharmacogenetic ‘Restriction-of-Function’ Approach Reveals Evidence for Anxiolytic-Like Actions Mediated by α5-Containing GABAA Receptors in Mice

Behlke

Foster

Liu

et al. 2016

Neuropsychopharmacol

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“…One possible candidate is GABA, the most common inhibitory neurotransmitter in our nervous system (Steighart, 1995). Animal studies suggest that GABA plays an important role in learning (Botta et al, 2015;Jovasevic et al, 2015). Importantly, there is evidence that prediction error signalling during learning seems to involve GABA (Kim et al, 1998).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Polymorphisms that affect GABA neurotransmission predict processing of aversive prediction errors in humans

et al. 2018

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Learning is one of our most adaptive abilities, allowing us to adjust our expectations about future events. Aberrant learning processes may underlie disorders such as anxiety, motivating the search for the neural mechanisms that underpin learning. Animal studies have shown that the neurotransmitter GABA is required for the computation of prediction errors, the mismatches between anticipated and experienced outcomes, which drive new learning. Given that evidence from human studies is lacking, we sought to determine whether these findings extend to humans. Here, in two samples of Caucasian individuals, we investigated whether genetically determined individual differences in GABA neurotransmission predict the P3 event-related potential, an EEG component known to reflect prediction error processing.Consistent with the results of animal studies, we show that a weighted genetic risk score computed from the number of GABRB2 rs1816072 A alleles (associated with increased expression of the GABAA receptor β2 subunit gene) and the number of ErbB4 rs7598440 T alleles (associated with increased GABA concentration) predicts optimal prediction error processing during aversive classical conditioning with both visual (Experiment 1, N = 90; p = .010) and auditory (Experiment 2; N = 92; p = .031) unconditioned stimuli. Our finding that optimal processing of aversive prediction errors is reduced in individuals genetically predisposed towards decreased GABA neurotransmission suggests a potential mechanism linking GABA and anxiety. Specifically, reduced GABA signalling via GABAA receptors could result in aberrant learning from aversive experiences and vulnerability to anxiety disorders.

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“…However, the relations are not straightforward; for instance, high activity at α1-GABAA-Rs induces sedation and contributes to amnesia, but the same receptor subtype is also implicated in cognition by co-localizing with α5 and γ2 subunits [15]. The BZ anxiolytic properties are mediated predominantly by α2-GABAA-Rs [16] and also by α5-GABAA-Rs [17, 18]. Selective activity at α5-GABAA-Rs has also been suggested to play a critical role in alleviating “behavioral emotionality” (anxiety and depressive-like behaviors) in a mouse model of depression (using chronic stress in mice [19]) or cognitive dysfunctions in mouse models of schizophrenia [20] or in old rats [21].…”

Section: Introductionmentioning

confidence: 99%

Novel Benzodiazepine-Like Ligands with Various Anxiolytic, Antidepressant, or Pro-Cognitive Profiles

Prevot¹,

Vidojević

et al. 2019

Complex Psychiatry

124

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Altered gamma-aminobutyric acid (GABA) function is consistently reported in psychiatric disorders, normal aging, and neurodegenerative disorders and reduced function of GABA interneurons is associated with both mood and cognitive symptoms. Benzodiazepines (BZ) have broad anxiolytic, but also sedative, anticonvulsant and amnesic effects, due to nonspecific GABA-A receptor (GABAA-R) targeting. Varying the profile of activity of BZs at GABAA-Rs is predicted to uncover additional therapeutic potential. We synthesized four novel imidazobenzodiazepine (IBZD) amide ligands and tested them for positive allosteric modulation at multiple α-GABAA-R (α-positive allosteric modulators), pharmacokinetic properties, as well as anxiolytic and antidepressant activities in adult mice. Efficacy at reversing stress-induced or age-related working memory deficits was assessed using a spontaneous alternation task. Diazepam (DZP) was used as a control. Three ligands (GL-II-73, GL-II-74, and GL-II-75) demonstrated adequate brain penetration and showed predictive anxiolytic and antidepressant efficacies. GL-II-73 and GL-II-75 significantly reversed stress-induced and age-related working memory deficits. In contrast, DZP displayed anxiolytic but no antidepressant effects or effects on working memory. We demonstrate distinct profiles of anxiolytic, antidepressant, and/or pro-cognitive activities of newly designed IBZD amide ligands, suggesting novel therapeutic potential for IBZD derivatives in depression and aging.

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Regulating anxiety with extrasynaptic inhibition

Cited by 168 publications

References 34 publications

A Pharmacogenetic ‘Restriction-of-Function’ Approach Reveals Evidence for Anxiolytic-Like Actions Mediated by α5-Containing GABAA Receptors in Mice

A Pharmacogenetic ‘Restriction-of-Function’ Approach Reveals Evidence for Anxiolytic-Like Actions Mediated by α5-Containing GABAA Receptors in Mice

Polymorphisms that affect GABA neurotransmission predict processing of aversive prediction errors in humans

Novel Benzodiazepine-Like Ligands with Various Anxiolytic, Antidepressant, or Pro-Cognitive Profiles

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