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Reduction of zolpidem sensitivity in a freeze lesion model of neocortical dysgenesis
1Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Abstract:
Early postnatal freeze lesions in rat neocortex produce anatomic abnormalities resembling those observed in human patients with seizure disorders. Although in vitro brain slices containing the lesion are hyperexcitable, the mechanisms of this alteration have yet to be elucidated. To test the hypothesis that changes in postsynaptic inhibitory receptors may underlie this hyperexcitability, we examined properties of gamma-aminobutyric acid type A receptor (GABAAR)-mediated miniature inhibitory postsynaptic currents (mIPSCs). Recordings were obtained in layer II/III pyramidal cells located 1-2 mm lateral to the lesion. mIPSC peak amplitude and rate of rise were increased relative to nonlesioned animals, whereas decay time constant and interevent interval were unaltered. Bath application of zolpidem at a concentration (20 nM) specific for activation of the type 1 benzodiazepine receptor had no significant effect on decay time constant in six of nine cells. Exposure to higher concentrations (100 nM) enhanced the decay time constant of all cells tested (n = 7). Because mIPSCs from unlesioned animals were sensitive to both concentrations of zolpidem, these results suggest that freeze lesions may decrease the affinity of pyramidal cell GABAARs for zolpidem. This could be mediated via a change in alpha-subunit composition of the GABAAR, which eliminates the type 1 benzodiazepine receptor.
Insights
Early brain freeze lesions in rats cause abnormal anatomy and hyperexcitability. These changes in gamma-aminobutyric acid type A receptors (GABAARs) may explain seizure disorder similarities.
Area of Science:
- Neuroscience
- Pathology
Background:
- Early postnatal freeze lesions in rat neocortex induce abnormalities similar to human seizure disorders.
- Brain slices with lesions exhibit hyperexcitability, but the underlying mechanisms are unclear.
Purpose of the Study:
- To investigate if altered postsynaptic inhibitory receptors contribute to lesion-induced hyperexcitability.
- To examine the properties of gamma-aminobutyric acid type A receptor (GABAAR)-mediated miniature inhibitory postsynaptic currents (mIPSCs).
Main Methods:
- Electrophysiological recordings of mIPSCs in layer II/III pyramidal cells near the lesion.
- Analysis of mIPSC parameters including amplitude, rise time, decay time constant, and interevent interval.
- Pharmacological assessment using zolpidem to probe GABAAR benzodiazepine receptor subtypes.
Main Results:
- mIPSC peak amplitude and rate of rise were elevated in lesioned animals compared to controls.
- Decay time constant and interevent interval of mIPSCs remained unchanged.
- Freeze lesions appeared to decrease the affinity of pyramidal cell GABAARs for zolpidem, potentially by altering alpha-subunit composition and eliminating type 1 benzodiazepine receptors.
Conclusions:
- Freeze lesions alter GABAAR function in rat neocortex, contributing to hyperexcitability.
- Changes in GABAAR subunit composition may underlie the observed alterations in inhibitory neurotransmission.
- These findings offer insights into the mechanisms of seizure disorders associated with early brain injury.
