The Molecular Basis of Learning and Memory
Clearly at some point in development between the one-cell stage and the mature adult, an organism obtains the ability to learn and remember. It has been demonstrated that rodents, amphibians, primates, aves, and teleosts, all use the neurotransmitter glutamate in the learning and memory process. Glutamate binds the NMDA receptor and triggers activation of neurons involved in the physiological processes for learning and memory. The NR1 protein is required for building the NMDA neurotransmitter receptor. Multiple splice variants are expressed from the NR1 gene. The NR1 protein contains an N1 cassette and from one to three C-terminal cassettes that can be alternatively spliced. The different splice variants respond differently to a given concentration of glutamate.

In our laboratory we are studying this system using Danio rerio (zebrafish) as a model organism. They have proved to be an ideal model system in that their genes for encoding the NMDA proteins are very similar to humans and they are extremely easy organisms to work with in the laboratory. We have developed assays to test for the presence of the N1 cassette from zebrafish cDNA. We can therefore track the presence of the NR1 transcript and its splice variants over the course of development from the unfertilized egg through to the adult fish. In addition, we are interested in determining exactly which regions in the brain express the NR1 mRNA and protein. Taken together we should get a good picture of where and when the NR1 transcript and its N1 splice variant are produced and where the protein is expressed. Ultimately we would like to determine the role of the different splice variants in the learning and memory process.

Infectious Disease
Scientists believe that tuberculosis kills more than 5000 people a day in the developing world. Many in America have lost sight of the world-wide epidemic, because in large part this is a curable disease. Most TB in the United States is cured by a six-month to yearlong course of antibiotics. Many in the US are working to try to bring these treatments to infected individuals in the developing world. The developing world however is developing new strains of Mycobacterium tuberculosis that cannot be treated by the current drug regiment. In ISROP we are studying genes that potentially allow Mycobacterium tuberculosis to evade our immune system and therefore become pathogenic when inhaled. Our hope is that we will find new targets for antibiotic development. Previous ISROP research culminated in a phylogenetic characterization of all of the known NADP+–dependent isocitrate dehydrogenase (ICDH) enzymes, more than 200 sequences from organisms including bacteria, plants, fungi, protists, and animals. One interesting outcome from that phylogenetic study was that Mycobacterium tuberculosis carried an ICDH gene that was unlike most bacterial genes and instead related to a eukaryotic ICDH that could potentially protect the M. tuberculosis from the assaults of our immune system. We are currently testing the hypothesis that M. tuberculosis uses its ICDH enzyme to protect itself from the oxidative damage of the human immune system, allowing it to avoid death within human macrophage. While we obviously are not able to work with the pathogenic M. tuberculosis strain on the Bard College campus, much of the work can be done using the non-pathogenic Mycobacterium smegmatis strain. In addition we can do all of the genetic manipulations on the isolated M. tuberculosis DNA and then collaborate with our colleagues in John McKinney’s laboratory at The Rockefeller University for work with pathogenic strains.