Presynaptic modulation controlling neuronal excitability and epileptogenesis: role of kainate, adenosine and neuropeptide Y receptors.

Based on the idea that seizures may arise from an overshoot of excitation over inhibition, all substances that may decrease glutamatergic function while having no effect or even increasing GABAergic neurotransmission are likely to be effective anticonvulsants. We now review the possible role of three such neuromodulators, kainate, adenosine, and neuropeptide Y receptors in controlling hyperexcitability and epileptogenesis. Particular emphasis is given on the robust neuromodulatory role of these three groups of receptors on the release of glutamate in the hippocampus, a main focus of epilepsy. Moreover, we also give special attention to the mechanisms of receptor activation and coupled signaling events that can be explored as attractive targets for the treatment of epilepsy and excitotoxicity. The present paper is a tribute to Arsélio Pato de Carvalho who has been the main driving force for the development of Neuroscience in Portugal, notably with a particular emphasis on the presynaptic mechanisms of modulation of neurotransmitter release.