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Neuroactive steroids alphaxalone and CDNC24 are effective hypnotics and potentiators of GABA_A currents, but are not neurotoxic to the developing rat brain.

ABSTRACT:

Background

The most currently used general anaesthetics are potent potentiators of γ-aminobutyric acid A (GABA_A) receptors and are invariably neurotoxic during the early stages of brain development in preclinical animal models. As causality between GABA_A potentiation and anaesthetic-induced developmental neurotoxicity has not been established, the question remains whether GABAergic activity is crucial for promoting/enhancing neurotoxicity. Using the neurosteroid analogue, (3α,5α)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), which potentiates recombinant GABA_A receptors, we examined whether this potentiation is the driving force in inducing neurotoxicity during development.

Methods

The neurotoxic potential of CDNC24 was examined vis-à-vis propofol (2,6-diisopropylphenol) and alphaxalone (5α-pregnan-3α-ol-11,20-dione) at the peak of rat synaptogenesis. In addition to the morphological neurotoxicity studies of the subiculum and medial prefrontal cortex (mPFC), we assessed the extra-, pre-, and postsynaptic effects of these agents on GABAergic neurotransmission in acute subicular slices from rat pups.

Results

CDNC24, like alphaxalone and propofol, caused dose-dependent hypnosis in vivo, with a higher therapeutic index. CDNC24 and alphaxalone, unlike propofol, did not cause developmental neuroapoptosis in the subiculum and mPFC. Propofol potentiated post- and extrasynaptic GABA_A currents as evidenced by increased spontaneous inhibitory postsynaptic current (sIPSC) decay time and prominent tonic currents, respectively. CDNC24 and alphaxalone had a similar postsynaptic effect, but also displayed a strong presynaptic effect as evidenced by decreased frequency of sIPSCs and induced moderate tonic currents.

Conclusions

The lack of neurotoxicity of CDNC24 and alphaxalone may be at least partly related to suppression of presynaptic GABA release in the developing brain.

SUBMITTER: Tesic V

PROVIDER: S-EPMC7222221 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Although NPY has potent anxiolytic actions within the BLA, selective activation of BLA NPY Y2 receptors (Y2Rs) acutely increases anxiety by an unknown mechanism. Using ex vivo male rat brain slice electrophysiology, we show that the selective Y2R agonist, [ahx5-24]NPY, reduced the frequency of GABAA-mediated mIPSCs in BLA principal neurons (PNs). [ahx5-24]NPY also reduced tonic activation of GABAB receptors (GABABR), which increased PN excitability through inhibition of a tonic, inwardly rectifying potassium current (KIR ). Surprisingly, Y2R-sensitive GABABR currents were action potential-independent, persisting after treatment with TTX. Additionally, the Ca2+-dependent, slow afterhyperpolarizing K+ current (IsAHP ) was enhanced in approximately half of the Y2R-sensitive PNs, possibly from enhanced Ca2+ influx, permitted by reduced GABABR tone. In male and female mice expressing tdTomato in Y2R-mRNA cells (tdT-Y2R mice), immunohistochemistry revealed that BLA somatostatin interneurons express Y2Rs, as do a significant subset of BLA PNs. In tdT-Y2R mice, [ahx5-24]NPY increased excitability and suppressed the KIR in nearly all BLA PNs independent of tdT-Y2R fluorescence, consistent with presynaptic Y2Rs on somatostatin interneurons mediating the above effects. However, only tdT-Y2R-expressing PNs responded to [ahx5-24]NPY with an enhancement of the IsAHP Ultimately, increased PN excitability via acute Y2R activation likely correlates with enhanced BLA output, consistent with reported Y2R-mediated anxiogenesis. Furthermore, we demonstrate the following: (1) a novel mechanism whereby activity-independent GABA release can powerfully dampen BLA neuronal excitability via postsynaptic GABABRs; and (2) that this tonic inhibition can be interrupted by neuromodulation, here by NPY via Y2Rs.SIGNIFICANCE STATEMENT Within the BLA, NPY is potently anxiolytic. However, selective activation of NPY2 receptors (Y2Rs) increases anxiety by an unknown mechanism. We show that activation of BLA Y2Rs decreases tonic GABA release onto BLA principal neurons, probably from Y2R-expressing somatostatin interneurons, some of which coexpress NPY. This increases principal neuron excitability by reducing GABAB receptor (GABABR)-mediated activation of G-protein-coupled, inwardly rectifying K+ currents. Tonic, Y2R-sensitive GABABR currents unexpectedly persisted in the absence of action potential firing, revealing, to our knowledge, the first report of substantial, activity-independent GABABR activation. Ultimately, we provide a plausible explanation for Y2R-mediated anxiogenesis in vivo and describe a novel and modulatable means of damping neuronal excitability.

Project description:Synaptic and extrasynaptic GABAA receptor (GABAAR)-mediated neurotransmission is a critical component of the suprachiasmatic nucleus (SCN) neuronal network. However, the properties of the GABAA tonic current (Itonic) and its origin remain unexplored. Spontaneous GABAA postsynaptic currents (sGPSCs) and Itonic were recorded from SCN neurons with the whole cell voltage-clamp technique at different times of the day. GABAAR antagonists (bicuculline, gabazine, and picrotoxin) inhibited sGPSC and induced an outward shift of the holding current, which defined the Itonic amplitude. The sGPSC frequency, synaptic charge transfer, and Itonic amplitude all demonstrated significant diurnal rhythms, with peaks in the middle of the day [zeitgeber time (ZT)7-8] and nadirs at night (ZT19-20). The Itonic amplitude increased proportionally with the sGPSC frequency and synaptic charge transfer during the day and required action potential-mediated GABA release, which was confirmed by TTX application. The activation of presynaptic GABAB receptors by baclofen did not significantly alter the Itonic of neurons with low-frequency sGPSC. The equilibrium potential (Eq) for Itonic was similar to the Eq for chloride and GABAA receptor-activated currents. Itonic showed outward rectification at membrane potentials over the range of -70 to -10 mV and then was linear at voltages greater than -10 mV. GABAAR containing α4-, α5-, and δ-subunits were expressed in SCN, and their contribution to Itonic was confirmed by application of the GABAAR agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) and the GABAAR inverse agonist 11,12,13,13a-tetrahydro-7-methoxy-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid ethyl ester (L655,708). Thus, the Itonic was mediated by extrasynaptic GABAARs activated predominantly by GABA diffusing out of GABAergic synapses.NEW & NOTEWORTHY A tonic current (Itonic) mediated by GABAA receptors (GABAARs) containing α4-, α5- and δ-subunits was observed in the suprachiasmatic nucleus. The Itonic amplitude strongly depended on the action potential-mediated synaptic release of GABA. The equilibrium potential for Itonic corresponds to that for GABAA currents. The frequency of GABAA postsynaptic currents and Itonic amplitude increased during the day, with peak in the middle of the day, and then gradually declined with a nadir at night, thus showing a diurnal rhythm.

Dataset Information

Neuroactive steroids alphaxalone and CDNC24 are effective hypnotics and potentiators of GABA_A currents, but are not neurotoxic to the developing rat brain.

Background

Methods

Results

Conclusions

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Neuroactive steroids alphaxalone and CDNC24 are effective hypnotics and potentiators of GABAA currents, but are not neurotoxic to the developing rat brain.

Background

Methods

Results

Conclusions

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Neuroactive steroids alphaxalone and CDNC24 are effective hypnotics and potentiators of GABA_A currents, but are not neurotoxic to the developing rat brain.