Final Report Summary - HIPPOKAR (Understanding the roles of kainate receptors in the hippocampus)
L-Glutamate is the principal excitatory neurotransmitter in the mammalian brain and as such is responsible for chemical communication for the majority of the 10 trillion synapses in the human brain. Understanding glutamatergic transmission is therefore if extreme importance for the understanding if brain function in health and disease. L-glutamate acts via four main classes of proteins molecules, called receptors; the least well understood of which is the kainate receptor. Our project explores the function of kainate receptors in the brain of rodents. We are using a highly multidisciplinary strategy involving chemists, mouse geneticists, biochemists, pharmacologists and physiologists to advance this field in several directions. We are developing novel tools (chemical reagents and mouse lines) that will of use to the worldwide research community for understanding the functions of kainate receptors in the brain. We are using these tools, plus existing tools, to understand the function of kainate receptors in a region of the brain known as the hippocampus. This brain region is critically involved in learning and memory and damage to the hippocampus is associated with cognitive deficits in a wide range of brain disorders, including dementia, temporal-lobe epilepsy and stroke-induced brain injury. We are testing several specific hypothesizes regarding the role of kainate receptors in the hippocampus in the brains of rats and mice, using both in vitro and in vivo methodologies. Our primarily goal is to understand the location and function of the kainate receptors that are concentrated in the CA3 region of the hippocampus. These receptors are localized on both the neurons within the CA3 hippocampal subfield and on the inputs originating from another region of the hippocampal formation, the dentate gyrus, via the mossy fibre pathway. We have discovered that one type of kainate receptor, that contains a specific protein constituent known as the GluK1 subunit, is particularly important for regulating the magnitude of the signal from the dentate gyrus to the CA3 region, over a period of time ranging from fractions of a second to in excess of hours. We have generated a novel mouse line that specifically lacks this subunit only at this site within the hippocampal formation and are well advanced in making a similar mouse line lacking the GluK3 subunit. We have also made the most potent and specific compounds for exploring the role of the GluK1 subunit using pharmacological techniques and have made lead compounds for the development of specific GluK2 antagonists.