Elsevier

Neuropharmacology

Volume 36, Issue 6, June 1997, Pages 823-830
Neuropharmacology

Modulation of Long-term Potentiation in CA1 Region of Mouse Hippocampal Brain Slices by GABAA Receptor Benzodiazepine Site Ligands

https://doi.org/10.1016/S0028-3908(97)00040-3Get rights and content

Abstract

Enhancement of GABAA receptor function with benzodiazepine (BZ) site agonists can disrupt memory formation and hippocampal synaptic plasticity. To investigate this further the effects of the agonist, flunitrazepam, were contrasted with that of the inverse agonist, methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), on NMDA-dependent LTP induction in the CA1 region of mouse hippocampus. Under control conditions, a priming stimulus (10 stimuli at 100 Hz) potentiated e.p.s.p. slopes by 198%, and subsequent burst stimuli (4 × 10 events at 100 Hz every 20 sec) by 306%. This potentiation was blocked by the non-competitive NMDA receptor antagonist MK-801 and the glycine site antagonist L-701,324. Flunitrazepam (1 μM) alone caused a slight but significant reduction in e.p.s.p.s to 83% of control, suppressed LTP induced by priming stimuli (133%) and burst stimuli (188%), but not that induced by sustained high-frequency stimulation (2 × 100 events at 100 Hz, 20 sec apart). The suppression of LTP induction by flunitrazepam was blocked by the benzodiazepine site antagonist flumazenil. In contrast, the inverse agonist DMCM (100 nM) potentiated LTP formed by both priming (to 283%) and burst stimuli (to 477%). This was associated with an enhancement of paired pulse facilitation during the induction phase and the subsequent appearance of paroxysmal burst discharges. Therefore, in addition to improvements in learning and memory as a result of improved vigilance, benzodiazepine inverse agonists can have direct effects on synaptic processes thought to contribute to memory formation. © Elsevier Science Ltd.

Section snippets

MATERIALS AND METHODS

Extracellular recordings were made from the stratum radiatum in the CA1 region of mouse hippocampal brain slices. Slices (300–350 μm thick) were prepared from male C57 mice (20–40 weeks old) using methods as described previously for rat brain (Kemp et al., 1986). In brief, parasaggittal slices were submerged in a tissue chamber (volume 0.4 ml) by a continuously superfused (at 1–2 ml/min) artificial cerebrospinal fluid (ACSF) kept at 35°C and gassed with 95% O2/5% CO2. The ACSF contained (in

RESULTS

Excitatory postsynaptic potentials (e.p.s.p.s) in the stratum radiatum of the CA1 hippocampal region were elicited by orthodromic stimulation of the Schaffer collateral pathway with bipolar tungsten stimulating electrodes (5–50 V for a duration of 0.02 msec at 0.033 Hz). The effects of drugs on the induction of LTP by priming stimulus frequencies (priming stimulus; 10 events at 100 Hz) was compared with that induced by bursts of high-frequency stimuli (burst stimuli; 4 × 10 events at 100 Hz

DISCUSSION

This study provides further evidence that modulation of GABAA receptor function with benzodiazepines can regulate the plasticity of synaptic transmission from the Schaffer collateral commissural pathway to CA1 region of mouse hippocampus. The BZ agonist, flunitrazepam, suppressed the induction of long-term potentiation in a stimulus-dependent manner, whereas the inverse agonist DMCM facilitated its induction.

LTP was first described in vivo in the perforant path to dentate gyrus of rabbit

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