Role of kainate receptors in olfactory learning
Zusammenfassung der Projektergebnisse
The major aim of our proposal was to describe the cellular and molecular mechanism underlying complex learning. Based on our previous studies and preliminary data presented here, we hypothesized that activation of the GluR6- subtype (also termed GluK2) kainateactivated glutamate receptor has a central role in rule learning (learning how to learn). To bridge the gap between behavioral phenomena and events that occur at the cellular and sub cellular levels, we undertook a top-bottom-top approach with the ultimate goal of drawing a comprehensive model of the mechanisms underlying rule learning. If our hypothesis is proved right, results of the research may be beneficial for developing specific molecular tools that would then be applied to enhance learning in general. Such tools would be also instrumental in mending cognitive decline induced by aging or neurodegenerative diseases. In our previous studies we found evidence showing that complex learning, termed 'rule learning' or 'learning set', is mediated by enhanced intrinsic neuronal excitability; the acquisition of complex rules requires modifications in the neurons' properties, which enable them to increase their sustained spike firing rate, thus allowing them to significantly enhance their ability to transmit and process information. Moreover, we identified a key biophysical modification that mediates such enhancement. It is the shutdown of a particular calciumdependent potassium current, termed the "slow after hyper-polarization" (sIAHP). In this proposal we combined behavioral studies with single cell intracellular recordings and genetic manipulations, to examine whether GluR6 is the key molecule that triggers the chain of events leading to specific reduction in the sIAHP current and subsequently to rule learning. In the first part of the proposal we tested if kainate-receptors, particularly GluR6 activation results with enhanced intrinsic neuronal excitability, identical to that detected after complex learning. In the second part we examined if there is a causal relation between Glur6 activation and enhanced 'rule learning' capabilities. Based on our results we are now engaged in the process of developing a cognitive enhancer that will act by specific activation of the receptor.
