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Neurosteroid effects on GABAergic synaptic plasticity in hippocampus
Fu-Chun Hsu1, Robert Waldeck, Donald S Faber
1Department of Neurobiology and Anatomy, Medical College of Pennsylvania-Hahnemann University, Philadelphia, Pennsylvania 19129, USA.
Journal of Neurophysiology
|March 4, 2003
Summary
Short-term steroid exposure (3alpha,5alpha-THP) increases alpha4 subunit expression in GABA(A) receptors (GABARs) in rat hippocampus. This accelerates inhibitory current decay, potentially increasing neuronal excitability.
Area of Science:
- Neuroscience
- Neuropharmacology
- Cellular Electrophysiology
Background:
- Short-term exposure to the GABA-modulatory steroid 3alpha,5alpha-THP increases alpha4 subunit expression in hippocampal GABA(A) receptors (GABARs).
- This alteration in GABAR composition accelerates inhibitory current decay and increases neuronal excitability.
- The precise synaptic localization mediating these kinetic changes remains to be elucidated.
Purpose of the Study:
- To investigate whether synaptic GABARs mediate the accelerated kinetics observed after short-term steroid treatment.
- To determine the role of the alpha4 subunit in mediating these effects on GABAR kinetics.
- To explore the implications of altered GABAR kinetics for hippocampal excitability.
Main Methods:
- Electrophysiological recordings of TTX-resistant miniature inhibitory postsynaptic currents (mIPSCs) in CA1 pyramidal cells from rat hippocampal slices.
- Treatment with 3alpha,5alpha/beta-THP and assessment of mIPSC decay kinetics.
- Pharmacological manipulation using antisense oligonucleotides to suppress alpha4 subunit expression and benzodiazepine agonists (RO15-4513, lorazepam).
Main Results:
- 48-h treatment with 3alpha,5alpha/beta-THP significantly accelerated the fast decay time constant (tau(fast)) of GABAergic mIPSCs.
- Suppression of alpha4 subunit expression with antisense oligonucleotide prevented this acceleration, indicating alpha4-containing GABARs are involved.
- Pharmacological data suggested that alpha4-containing GABARs are located subsynaptically and contribute to the observed kinetic changes.
Conclusions:
- Short-term 3alpha,5alpha/beta-THP administration increases alpha4-containing GABARs at subsynaptic sites in the hippocampus.
- The accelerated decay kinetics of GABAergic currents due to these changes may lead to decreased inhibitory charge transfer.
- This reduction in inhibition likely contributes to the observed increase in hippocampal neuronal excitability.