GABAB receptor isoforms differentially modulate the CA1 population spikes and field EPSPs in the hippocampal slices

Irina Vinogradova, Ying Chen. University of Surrey, Guildford, United Kingdom.

Activation of metabotropic GABAB receptors modulates synaptic transmission at both pre- and post-synaptic sites. In the GABAB1a-/- or GABAB1b-/- mice, the 1a and 1b isoforms were found to localize differentially on the presynaptic glutamateric terminals and postsynaptic sites, respectively (Vigot et al., 2006). The aims of the present study were to investigate the modulation of CA1 population spikes (PSs) and field EPSPs (fEPSPs) by the selective activation of GABAB receptor isoforms in the 1a-/- and 1b-/- mice and the modulation of GABAB receptor isoforms by the positive allosteric modulator CGP7930. PSs and fEPSPs were recorded from a number of positions in the CA1 pyramidal layer and stratum radiatum correspondingly in response to paired stimuli (15 ms interval, 100-140 μA maximal intensity and 0.2 ms duration) applied to Schaffer collaterals. PS input-output (I-O) curves were indistinguishable between GABAB1a-/- and GABAB1b-/- mutants but they were significantly different from the I-O curve for wild type mice. However, GABAB receptor antagonist CGP55845 (1-3 μM) did not shift the I-O curve in wild type mice. GABAB receptor activation by baclofen suppressed both PSs and fEPSPs in WT and GABAB1b-/- mice to a greater extent than in GABAB1a-/- with PSs being more sensitive to baclofen. The effects of baclofen could be reversed by GABAB receptor antagonist CGP55845, confirming the GABAB receptor-mediated effects.

The GABAB receptor allosteric potentiator, CGP7930, did not affect baclofen’s effects on either PSs or fEPSPse in WT and GABAB1b-/- mice. However, in brain slices of GABAB1a-/- mutants in the presence of the potentiator, baclofen caused significant decrease in PS amplitudes and fEPSP slopes as well as an increase in pair-pulse ratio of both PSs and fEPSPs. The results indicate that the GABAB receptor isoforms may be differentially modulated by CGP7930 as it has been suggested earlier (Chen et al, 2006). In addition, an enhanced EPSP-PS coupling is shown in the hippocampal CA1 neurones of the transgenic mice, demonstrating an enhanced intrinsic excitability.

Chen Y, Menendez-Roche N, Sher E. Pharmacol Exp Ther. 2006 Jun;317(3):1170-7.
Vigot R, Barbieri S, Bräuner-Osborne H, et al. Neuron. 2006 May 18; 50(4):589-601.

The gift of transgenic mice by Prof. Bernhard Bettler is gratefully acknowledged. Supported by BBSRC grant BB/E010296/1.