Derangement of calcium regulation in neuronal cells has many serious consequences that include not only the defect of learning and memory but also other neurological diseases such as epilepsy, stroke, and dementia or Alzheimer's disease. PLC betal-disrupted mutant mouse generated in Hee-Sup Shin's laboratory gives a good example because this mouse has acetylcholinergic signaling blocked, which is known to be important in the execution of learning and memory, and at the same time shows epilepsy. Therefore, the study on the mechanism of intracellular Ca2+ regulation has the importance in two aspects. First, in neuroscience, it will bring us closer to understanding the mechanism of learning and memory at the molecular, cellular, and neural levels. Second, in medicine, it will allow us to understand the pathogenesis of yet intractable neurological diseases. Towards these ends, Shin's group are trying to define the functions in vive of those genes involved in the regulation of intracellular Ca2+.
The primary efforts will be focused on generating knock-out mice for a variety of genes which are known to be involved in the regulation of intracellular Ca2+ concentration, and thereby clarifying their roles in learning and memory. In the initial stage, the relationship between the muscarinic acetylcholine receptor/PLC betal signaling system and learning and memory will be investigated in follow up of the previously obtained results. Eventually, a bigger picture showing; the regulation mode of learning and memory will be drawn up by putting together the information derived from studies of the interactions among a variety of genes. For those purposes, knock-out mice are currently being manufactured for several genes that include calcium channel genes, and six different mutants have already been generated and analyzed now. The other focus of research is to understand the pathogenesis of neurological diseases which are represented as phenotypes in the mutant mice. For these studies, a variety of tools will be mobilized including physiology, biochemistry, pharmacology, pathology, behavioral analysis, and clinical neurology in addition to genetic tools.