Dataset Information

Neurosteroids Mediate Neuroprotection in an In Vitro Model of Hypoxic/Hypoglycaemic Excitotoxicity via δ-GABA_A Receptors without Affecting Synaptic Plasticity.

ABSTRACT: Neurosteroids and benzodiazepines are modulators of the GABA_A receptors, thereby causing anxiolysis. Furthermore, benzodiazepines such as midazolam are known to cause adverse side-effects on cognition upon administration. We previously found that midazolam at nanomolar concentrations (10 nM) blocked long-term potentiation (LTP). Here, we aim to study the effect of neurosteroids and their synthesis using XBD173, which is a synthetic compound that promotes neurosteroidogenesis by binding to the translocator protein 18 kDa (TSPO), since they might provide anxiolytic activity with a favourable side-effect profile. By means of electrophysiological measurements and the use of mice with targeted genetic mutations, we revealed that XBD173, a selective ligand of the translocator protein 18 kDa (TSPO), induced neurosteroidogenesis. In addition, the exogenous application of potentially synthesised neurosteroids (THDOC and allopregnanolone) did not depress hippocampal CA1-LTP, the cellular correlate of learning and memory. This phenomenon was observed at the same concentrations that neurosteroids conferred neuroprotection in a model of ischaemia-induced hippocampal excitotoxicity. In conclusion, our results indicate that TSPO ligands are promising candidates for post-ischaemic recovery exerting neuroprotection, in contrast to midazolam, without detrimental effects on synaptic plasticity.

SUBMITTER: Puig-Bosch X

PROVIDER: S-EPMC10219454 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Neurosteroids Mediate Neuroprotection in an In Vitro Model of Hypoxic/Hypoglycaemic Excitotoxicity via δ-GABA<sub>A</sub> Receptors without Affecting Synaptic Plasticity.

Puig-Bosch Xènia X Ballmann Markus M Bieletzki Stefan S Antkowiak Bernd B Rudolph Uwe U Zeilhofer Hanns Ulrich HU Rammes Gerhard G

International journal of molecular sciences 20230521 10

Neurosteroids and benzodiazepines are modulators of the GABA<sub>A</sub> receptors, thereby causing anxiolysis. Furthermore, benzodiazepines such as midazolam are known to cause adverse side-effects on cognition upon administration. We previously found that midazolam at nanomolar concentrations (10 nM) blocked long-term potentiation (LTP). Here, we aim to study the effect of neurosteroids and their synthesis using XBD173, which is a synthetic compound that promotes neurosteroidogenesis by bindin ...[more]

PMID: 37240402

Similar Datasets

Project description:Key pointsCurrent views suggest γ2 subunit-containing GABAA receptors mediate phasic IPSCs while extrasynaptic δ subunits mediate diffusional IPSCs and tonic current. We have re-examined the roles of the two receptor populations using mice with picrotoxin resistance engineered into receptors containing the δ subunit. Using pharmacological separation, we find that in general δ and γ IPSCs are modulated in parallel by manipulations of transmitter output and diffusion, with evidence favouring modestly more diffusional contribution to δ IPSCs. Our findings also reveal that spontaneous δ IPSCs are mainly driven by channel deactivation, rather than by diffusion of GABA. Understanding the functional contributions of the two receptor classes may help us understand the actions of drug therapies with selective effects on one population over the other.AbstractGABAA receptors mediate transmission throughout the central nervous system and typically contain a δ subunit (δ receptors) or a γ2 subunit (γ2 receptors). δ IPSCs decay slower than γ2 IPSCs, but the reasons are unclear. Transmitter diffusion, rebinding, or slow deactivation kinetics of channels are candidates. We used gene editing to confer picrotoxin resistance on δ receptors in mice, then pharmacologically isolated δ receptors in mouse dentate granule cells to explore IPSCs. γ2 and δ components of IPSCs were modulated similarly by presynaptic manipulations and manipulations of transmitter lifetime, suggesting that GABA release recruits δ receptors proportionally to γ2 receptors. δ IPSCs showed more sensitivity to altered transmitter release and to a rapidly dissociating antagonist, suggesting an additional spillover contribution. Reducing GABA diffusion with 5% dextran increased the peak amplitude and decreased the decay of evoked δ IPSCs but had no effect on δ or dual-component (mainly γ2-driven) spontaneous IPSCs, suggesting that GABA actions can be local for both receptor types. Rapid application of varied [GABA] onto nucleated patches from dentate granule cells demonstrated a deactivation rate of δ receptors similar to that of δ spontaneous IPSCs, consistent with the idea that deactivation and local GABA actions drive δ spontaneous IPSCs. Overall, our results indicate that δ IPSCs are activated by both synaptic and diffusional GABA. Our results are consistent with a functional relationship between δ and γ2 GABAA receptors akin to that of slow NMDA and fast AMPA EPSCs at glutamate synapses.

Dataset Information

Neurosteroids Mediate Neuroprotection in an In Vitro Model of Hypoxic/Hypoglycaemic Excitotoxicity via δ-GABA_A Receptors without Affecting Synaptic Plasticity.

Publications

Neurosteroids Mediate Neuroprotection in an In Vitro Model of Hypoxic/Hypoglycaemic Excitotoxicity via δ-GABA<sub>A</sub> Receptors without Affecting Synaptic Plasticity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Neurosteroids Mediate Neuroprotection in an In Vitro Model of Hypoxic/Hypoglycaemic Excitotoxicity via δ-GABAA Receptors without Affecting Synaptic Plasticity.

Publications

Neurosteroids Mediate Neuroprotection in an In Vitro Model of Hypoxic/Hypoglycaemic Excitotoxicity via δ-GABA<sub>A</sub> Receptors without Affecting Synaptic Plasticity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Neurosteroids Mediate Neuroprotection in an In Vitro Model of Hypoxic/Hypoglycaemic Excitotoxicity via δ-GABA_A Receptors without Affecting Synaptic Plasticity.