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Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
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Forskolin reverses the O-GlcNAcylation dependent decrease in GABAAR current amplitude at hippocampal synapses
Shekinah Phillips1,2, John C Chatham3, Lori L McMahon4,5
1Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
Scientific Reports
|July 29, 2024
Summary
Increased O-GlcNAcylation can reverse GABAergic inhibition depression. Heightened O-GlcNAcylation unmasks neurosteroid potentiation of GABAergic synaptic currents in hippocampal cells.
Area of Science:
- Neuroscience
- Cellular Biology
- Biochemistry
Background:
- Post-translational modifications, including phosphorylation and O-GlcNAcylation, critically regulate GABAergic transmission.
- O-GlcNAcylation, the addition of β-N-acetylglucosamine, impacts GABA receptor function.
- Previous work showed acute O-GlcNAcylation decreases GABAergic currents.
Purpose of the Study:
- To investigate the interaction between O-GlcNAcylation and phosphorylation in modulating GABAergic inhibitory postsynaptic currents (IPSCs).
- To determine if O-GlcNAcylation influences the effects of neurosteroids on GABAergic transmission.
Main Methods:
- Electrophysiological recordings of IPSCs in hippocampal principal cells.
- Pharmacological manipulation of O-GlcNAcylation and serine phosphorylation levels.
- Assessment of the effects of forskolin and neurosteroids (THDOC, progesterone) on IPSC amplitude.
Main Results:
- While forskolin alone did not alter baseline IPSC amplitude, prior O-GlcNAcylation enhancement unmasked a forskolin-dependent potentiation, reversing O-GlcNAc-induced depression.
- The potentiating effect of forskolin was independent of adenylate cyclase and protein kinase A.
- Increased O-GlcNAcylation also unmasked a potentiating effect of neurosteroids THDOC and progesterone in a subset of cells.
Conclusions:
- Heightened O-GlcNAcylation can alter the modulation of GABAergic transmission by other factors.
- Under elevated O-GlcNAcylation, the neurosteroid binding site on GABAA receptors may become more accessible, strengthening synaptic inhibition.
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