Neurosteroids increase tonic GABAergic inhibition in the lateral section of the central amygdala in mice

Romo-Parra, Héctor; Blaesse, Peter; Sosulina, Ludmila; Pape, Hans‐Christian

doi:10.1152/jn.00045.2015

Cited by 11 publications

(3 citation statements)

References 77 publications

(92 reference statements)

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“…This lack of effect of a GABA A PAM was unpredicted, and contrasts with reduced repetitive behaviors in BTBR and C58/J mice by a GABA B agonist (Silverman et al, 2015), requiring further investigation. Neuroactive steroids are being investigated for anxiolytic efficacy, based on their inhibition of tonic signaling via extrasynaptic GABA A receptors in the amygdala, a region critical for emotional behaviors (Cardinal et al 2002; Kuraoka and Nakamura 2006; Murray 2007; Phelps 2006; Romo-Parra et al 2015). To confirm that ganaxolone produced anxiolytic actions at the doses tested in our social and repetitive behavior assays, we tested the same acute dose of 20 mg/kg in B6 and BTBR mice for its activity on the elevated plus-maze.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the neuroactive steroid ganaxolone on social and repetitive behaviors in the BTBR mouse model of autism

et al. 2015

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Rationale Abnormalities in excitatory/inhibitory neurotransmission are hypothesized to contribute to autism spectrum disorder (ASD) etiology. BTBR, an inbred mouse strain, displays social deficits and repetitive self-grooming, offering face validity to ASD diagnostic symptoms. Reduced GABAergic neurotransmission in BTBR suggests that GABAA receptor positive allosteric modulators (PAMs) could improve ASD-relevant BTBR phenotypes. The neuroactive steroid ganaxolone acts as a PAM, displaying anticonvulsant properties in rodent epilepsy models and an anxiolytic-like profile in the elevated plus-maze. Objectives We evaluated ganaxolone in BTBR and C57BL/6J mice in standardized assays for sociability and repetitive behaviors. Open field and anxiety-related behaviors were tested as internal controls and for comparison with the existing neuroactive steroid literature. Results Ganaxolone improved aspects of social approach and reciprocal social interactions in BTBR, with no effect on repetitive self-grooming, and no detrimental effects in C57BL/6J. Ganaxolone increased overall exploratory activity in BTBR and C57BL/6J in the open field, social approach, and elevated plus-maze, introducing a confound for the interpretation of social improvements. Allopregnanolone and diazepam similarly increased total entries in the elevated plus-maze, indicating that behavioral activation may be a general property of GABAA receptor PAMs in these strains. Conclusions Ganaxolone shows promise for improving sociability. In addition, ganaxolone, as well as other GABAA receptor PAMs, enhanced overall BTBR activity. The translational implications of specific sociability improvements and non-specific behavioral activation by ganaxolone in the BTBR model remains to be determined. Future studies to explore whether PAMs provide a novel profile with unique benefits for ASD treatment will be worthwhile.

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Section: Discussionmentioning

confidence: 99%

Evaluation of the neuroactive steroid ganaxolone on social and repetitive behaviors in the BTBR mouse model of autism

et al. 2015

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“…It has been demonstrated that in dentate gyrus granule cells of hippocampus PKC regulates tonic GABA-dependent inhibitory conductance but has no significant impact on the GABA-independent effects of s-GABA A Rs (O’Neill and Sylantyev, 2018b). However, at a longer time scale it was repeatedly shown that PKC and Ca 2+ /calmodulin-dependent protein kinase II increase tonic inhibition in hippocampus and amygdala due to enhanced phosphorylation and membrane insertion of β3-containing GABA A Rs (Saliba et al, 2012; Modgil et al, 2017) and α4-containing GABA A Rs; this PKC action can be potentiated by neurosteroids such as THDOC (Abramian et al, 2010, 2014; Romo-Parra et al, 2015). In turn, s-GABA A Rs-mediated tonic inhibition in dentate gyrus granule cells is controlled by G-proteins: non-specific block of G-proteins by pertussis toxin decreases the tonic current via the reduction of the s-GABA A Rs opening frequency (O’Neill and Sylantyev, 2018b).…”

Section: Functional Properties Of S-gabarsmentioning

confidence: 98%

The Functional Role of Spontaneously Opening GABAA Receptors in Neural Transmission

O’Neill

Sylantyev

2019

Front. Mol. Neurosci.

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Ionotropic type of γ-aminobutyric acid receptors (GABA A Rs) produce two forms of inhibitory signaling: phasic inhibition generated by rapid efflux of neurotransmitter GABA into the synaptic cleft with subsequent binding to GABA A Rs, and tonic inhibition generated by persistent activation of extrasynaptic and/or perisynaptic GABA A Rs by GABA continuously present in the extracellular space. It is widely accepted that phasic and tonic GABAergic inhibition is mediated by receptor groups of distinct subunit composition and modulated by different cytoplasmic mechanisms. Recently, however, it has been demonstrated that spontaneously opening GABA A Rs (s-GABA A Rs), which do not need GABA binding to enter an active state, make a significant input into tonic inhibitory signaling. Due to GABA-independent action mode, s-GABA A Rs promise new safer options for therapy of neural disorders (such as epilepsy) devoid of side effects connected to abnormal fluctuations of GABA concentration in the brain. However, despite the potentially important role of s-GABA A Rs in neural signaling, they still remain out of focus of neuroscience studies, to a large extent due to technical difficulties in their experimental research. Here, we summarize present data on s-GABA A Rs functional properties and experimental approaches that allow isolation of s-GABA A Rs effects from those of conventional (GABA-dependent) GABA A Rs.

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“…Furthermore, the NK1R-induced inward current persisted during TTX-induced blockade of spike activity, suggesting a direct postsynaptic effect of the recorded CEl neuron. One intriguing possibility is NK1R-mediated stimulation of GABA A Rs at extrasynaptic sites in CEl neurons, which are activated by ambient GABA (Botta et al 2015;Romo-Parra et al 2015). Increasing activation of extrasynaptic GABA A Rs would lead to an increase in tonic inhibitory tone in the CEl synaptic circuitry, thereby adding a slow time course of SP modulation complementing the regulation of fast inhibitory synaptic GABAergic events.…”

Section: Discussionmentioning

confidence: 99%

Substance P excites GABAergic neurons in the mouse central amygdala through neurokinin 1 receptor activation

Sosulina

Strippel

Romo-Parra

et al. 2015

Journal of Neurophysiology

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HC. Substance P excites GABAergic neurons in the mouse central amygdala through neurokinin 1 receptor activation. J Neurophysiol 114: 2500 -2508, 2015. First published September 2, 2015; doi:10.1152/jn.00883.2014.-Substance P (SP) is implicated in stress regulation and affective and anxiety-related behavior. Particularly high expression has been found in the main output region of the amygdala complex, the central amygdala (CE). Here we investigated the cellular mechanisms of SP in CE in vitro, taking advantage of glutamic acid decarboxylase-green fluorescent protein (GAD67-GFP) knockin mice that yield a reliable labeling of GABAergic neurons, which comprise 95% of the neuronal population in the lateral section of CE (CEl). In GFP-positive neurons within CEl, SP caused a membrane depolarization and increase in input resistance, associated with an increase in action potential firing frequency. Under voltage-clamp conditions, the SP-specific membrane current reversed at Ϫ101.5 Ϯ 2.8 mV and displayed inwardly rectifying properties indicative of a membrane K ϩ conductance. Moreover, SP responses were blocked by the neurokinin type 1 receptor (NK1R) antagonist L-822429 and mimicked by the NK1R agonist [Sar 9 ,Met(O 2 ) 11 ]-SP. Immunofluorescence staining confirmed localization of NK1R in GFP-positive neurons in CEl, predominantly in PKC␦-negative neurons (80%) and in few PKC␦-positive neurons (17%). Differences in SP responses were not observed between the major types of CEl neurons (late firing, regular spiking, low-threshold bursting). In addition, SP increased the frequency and amplitude of GABAergic synaptic events in CEl neurons depending on upstream spike activity. These data indicate a NK1R-mediated increase in excitability and GABAergic activity in CEl neurons, which seems to mostly involve the PKC␦-negative subpopulation. This influence can be assumed to increase reciprocal interactions between CElon and CEloff pathways, thereby boosting the medial CE (CEm) output pathway and contributing to the anxiogenic-like action of SP in the amygdala. substance P; central amygdala; neurokinin type 1 receptor; PKC␦

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Neurosteroids increase tonic GABAergic inhibition in the lateral section of the central amygdala in mice

Abstract: Romo-Parra H, Blaesse P, Sosulina L, Pape HC. Neurosteroids increase tonic GABAergic inhibition in the lateral section of the central amygdala in mice.

Cited by 11 publications

References 77 publications

Evaluation of the neuroactive steroid ganaxolone on social and repetitive behaviors in the BTBR mouse model of autism

Evaluation of the neuroactive steroid ganaxolone on social and repetitive behaviors in the BTBR mouse model of autism

The Functional Role of Spontaneously Opening GABAA Receptors in Neural Transmission

Substance P excites GABAergic neurons in the mouse central amygdala through neurokinin 1 receptor activation

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