L-Glutamate (Glu), the major excitatory neurotransmitter of the central nervous system, mediates its effects by activating two types of receptors: receptor-channels (or ionotropic) and receptors linked to a cellular metabolism (or metabotropic, mGluRs). MGluRs are classified into three groups (I,II and III) according to their associated metabolism and agonist sensitivity.
Our studies have been focused on presynaptic mGluRs involved in the control of the glutamatergic transrnission in the CA1 area of the hippocampus. We have shown that both group II and group III presynaptic mGluRs could be involved in the control of the synaptic transmission. We have now examined the action of kainate (KA) group of ionotropic Glu receptors in this regulation. We found that KA induces a synaptic depression, likely via a presvnaptic mechanism, and an inward current in the postsynaptic neurone.
The aim of the project is to study the physiological role of the KA receptors that we have detected. This study will be carried out by using patch clamp technique in combination with confocal microscopy to investigate the intracellular Ca2+ concentration ([Ca2+]i) changes activated by these receptors. Firstly, we will characterize both the pre- and postsynaptic mechanisms associated to the activation of KA receptors. Using confocal microscopy we will study the regulation of [Ca2+]i by KA in the presynaptic terminals, since a depression of the synaptic current is often associated with the closure of a Ca2+ channel. We will also characterize in detail the postsynaptic current by studying in detail which ion is involved in its generation.
Secondly, we will characterize pharmacologically the KA receptors involved since molecular cloning studies have shown the existence of 5 distinct KA receptors subtypes (GluR5-7, KAI2). The pharmacological approach will involved newly synthetized antagonists but also neutralizing antibodies raised against these subtypes.
The final aim of these studies will be to discover the physiological relevance of these receptors. We will study firstly under which conditions they can be activated and, secondly, if their activation is of relevance in physiological phenomena occuring in the hippocampus as long term potentiation. To address these questions, the experimental approaches chosen are different stimulation paradigms of the afferents of CA1 neurones. The effect of these stimulations will studied on both the synaptic transmission and the [Ca2+]i in the postsynaptic neurone.