GABAB receptors in the hippocampus: allosteric modulation and receptor isoforms.

The GABAB receptors belong to a family of specialised brain signalling molecules sensing the inhibitory neurotransmitter GABA. The GABAB receptors have been shown to participate in essential functions of the nervous system, like pain sensation, reward and learning and memory, and are hence important therapeutic targets for various diseases, including spasticity, epilepsy, pain and addiction. Baclofen (Lioresal), a molecule that can activate the GABAB receptors, is a muscle relaxant and currently used clinically to treat spasticity. Recently, molecules were also identified to enhance the function of the GABAB receptors by an alternative way of allosteric modulation, and these molecules were found effective in treating addiction and anxiety in animal models. These GABAB receptor potentiators may, thus, become a new class of therapeutics for psychiatric and neurological disorders. However, the detailed mechanisms underlying the actions of these new GABAB potentiators are still poorly understood. In this basic scientific project, we designed a series of experiments aiming to elucidate the mechanisms of the GABAB potentiators in neuronal signalling. Detailed electrophysiological and pharmacological characterization combined with genetic manipulations on GABAB receptor expression will be carried out in the context of neuronal signalling in brain tissues. The further understanding of the GABAB receptor functional modulations will aid the development of newer and more effective drugs for psychiatric and neurological disorders with reduced side effects. Major pharmaceutical companies have shown keen interests in this new drug target.

This project aims to elucidate the mechanisms underlying GABAB receptor allosteric modulation in synaptic transmission in the hippocampus. GABAB receptor functional heterogeneity was hypothesised to underlie a differential effect on hippocampal synaptic transmission exerted by the GABAB allosteric modulator, CGP7930. Using whole cell voltage clamp recordings in hippocampal slices, the effects of CGP7930 will be examined at GABAB receptors located at different synaptic locations: pre- versus postsynaptic and auto- versus heteroreceptors, in the CA1 areas. Any functional heterogeneity in terms of allosteric modulation will then be identified at the receptors at different synaptic locations. The molecular substrate underlying the GABAB receptor heterogeneity is not yet confirmed, but the two major GABAB receptor isoforms, the 1a and 1b, were suggested to be strong candidates and they were shown to express differentially in the hippocampal CA1 area. Mice with the GABAB 1a or 1b selective deletions will thus be examined regarding the roles of each isoform in synaptic transmission and their responses to GABAB allosteric modulator and GABAB agonists. These results will allow us to elucidate whether the GABAB receptor functional heterogeneity, especially in allosteric modulation, is associated with a particular isoform and/or the expression locations of the isoforms. To demonstrate the physiological relevance of the GABAB allosteric modulation, we will examine the effects of an allosteric modulator on intrinsic GABAB receptor - mediated control of neuronal hyperexcitability and rhythmic activity at the hippocampal network level.