CANNABISTARG · Regulation of normal and pathological activity of cortical networks by cannabinoids: focus on direct modulation of inhibitory GABAA and glycine receptors

Cannabinoid signaling is ubiquitous in the brain, but until now the focus has been on G-protein coupled cannabinoid receptor (CB1R) mediated effects. Recently growing number of studies report that cannabinoids at physiologically relevant concentrations can modulate the functional properties of a number of ligand- and voltage-gated ion channels, independent of CB1R activation. However, so far the importance of this pathway in cannabinoid signaling remains largely underestimated. Our new findings show that cannabinoids can act as direct neuromodulators of the GABA and glycine receptors. The newly discovered direct interaction of cannabinoids with inhibitory receptors displays features which differ from the CB1R-dependent modulation, therefore it may have completely different, so far unexpected, impact on neuronal activity. It is generally accepted that the balance between synaptic excitation and synaptic inhibition is essential for network activity and information processing. Epilepsy is one of the most common neurological disorders affecting 2% of the world’s population, in which normal brain function is disrupted as a consequence of intensive and synchronous burst activity from neuron assemblies. At present ~30% of epileptics are not adequately controlled with conventional drugs due to development of tolerance and pharmacoresistance, therefore justifying the search for new antiepileptic targets.We hypothesized that direct modulation of inhibitory synaptic transmission by cannabinoids might have high impact on initiation and development of the epileptoform activity and may provide effective tools for controlling the network function.Using multidisciplinary approach within the proposed project we will investigate the molecular mechanisms underlying CB1R-independent interaction of cannabinoids and inhibitory receptors and the role of this interaction in the function of normal and epileptic cortical networks.