Dr. Konrad Talbot

Research Assistant Professor in Neurobiology

University of Pennsylvania

United States

Professional Summary

Professional TrainingDr. Talbot received his Ph.D. in behavioral neuroscience from UCLA in 1989. He then taught that subject as an assistant professor in psychology first at Mount St. Mary's College in California (1990-1995) and then St. Olaf College in Minnesota (1995-1997). At the latter college, Dr. Talbot introduced a seminar on biological psychiatry and began student-assisted research on Alzheimer Disease (AD) with postmortem tissue from controls donated by Immanuel-St. Joseph's Hospital in Mankato and from AD cases donated by the Alzheimer Research Center in St. Paul. That awakened an interest in pursuing full-time clinical research, which led Dr. Talbot to become a postdoctoral fellow in the Department of Pathology and Laboratory Medicine at the University of Pennsylvania (1997-2001). During that fellowship, he acquired the skills needed for research in molecular pathology and used them to study membrane pathology and insulin signaling abnormalities in AD. Given his earlier interests in the molecular basis of psychiatric disorders, Dr. Talbot accepted an invitation from Dr. Steven Arnold in 2001 to become a senior research investigator in his laboratory here in the Department of Psychiatry at the University of Pennsylvania. In that capacity, Dr. Talbot continued work on insulin signaling abnormalities in AD and began studying aspects of synaptic pathology in schizophrenia, especially depletion of a novel protein (dysbindin-1) encoded by a gene often found to be associated with schizophrenia. Those topics have been the focus of his research since his faculty appointment here in January, 2008.Expertise in Clinical NeuroscienceWhile trained broadly in behavioral neuroscience, Dr. Talbot's particular expertise lies in neuroanatomical and neurochemical analyses of the mammalian central nervous system. He is a long-term consultant on mouse and rat brain atlases and serves when needed as a dissector for the brain autopsy team of the Center for Neurodegenerative Research at the University of Pennsylvania. Apart from the various forms of light and electron microscopy, his primary technical skills are in anatomical and molecular techniques that reveal the morphology, input-output organization, and/or chemical character of neuronal networks mediating behavior. Dr. Talbot's research group has developed means of optimizing these methods applied to postmortem tissue, allowing detection in human tissue of small protein levels, fractionation of synaptosomes into pre- and post-synaptic elements, and quantification of chronically phosphorylated proteins within intact tissue sections. Building on his graduate training in animal behavior, Dr. Talbot has also helped set up mouse colonies for behavioral genetics studies relevant to schizophrenia research. His expertise has been called upon as a reviewer for journals such as Biological Psychiatry, Diabetes, Molecular Psychiatry, Schizophrenia Research and as chairman of symposia at the American College of Neuropsychopharmacology and the Society for Neuroscience.Current Research InterestsThe primary research interest of Dr. Talbot is discovery of pathological processes that contribute to disabling cognitive deficits in neurodegenerative and psychiatric disorders. He and his coworkers have found two candidates for such pathological processes as mentioned above, namely altered neuronal insulin signaling in AD and synaptic depletion of dysbindin-1 in schizophrenia. Dr. Talbot is thus leading research projects investigating both those phenomena as described below.(1) Insulin Signaling Dysregulation in Alzheimer DiseaseOver the last decade, an increasing number of studies have shown that (a) type 2 diabetes is a risk factor for AD, (b) gene and protein expression of upstream molecules in insulin signaling pathways are reduced in AD brains, and (3) the activated forms of those molecules are also reduced in such brains. The latter two findings have been interpreted as indicating impaired brain insulin signaling in AD, but they do not establish that the deduced impairment occurs in neurons, that it occurs downstream in the insulin signaling pathway, or that it contributes to the prominent cognitive deficits in AD. To address these possibilities, Dr. Talbot initiated a project testing upstream and downstream components of neuronal insulin signaling in a brain area which is affected early in AD (i.e., hippocampal field CA1) where damage markedly impairs memory. This project, funded by the Alzheimer Disease Association, has been conducted in collaboration with Drs. Steven Arnold and John Trojanowski here at the University of Pennsylvania and with Drs. David Bennett and Robert Wilson at Rush University in Chicago.The project studies postmortem tissue from two sets of cases. One is a set of elderly controls and AD cases from the Center for Neurodegenerative Disease Research at the University of Pennsylvania. The other is a set of normal elderly, mild cognitively impaired (MCI), and AD cases from the Religious Order Study run by Rush University in Chicago. Using quantitative immunohistochemistry and phospho-specific antibodies, Dr. Talbot and his colleagues demonstrated chronic changes in phosphorylation of both upstream and downstream insulin signaling molecules in hippocampal CA1 neurons in both sets of cases. Surprisingly, such changes were different in upstream versus downstream molecules of the insulin signaling pathway studied. The insulin receptor in AD showed reduced tyrosine phosphorylation, indicating chronically decreased receptor activation in AD. Yet the phosphorylation state of all downstream molecules in insulin signaling (e.g., Akt and GSK-3) indicated chronically increased activation of those molecules, consistent with evidence of increased feedback inhibition on the molecule (i.e., insulin receptor substrate 1, IRS-1) that controls downstream signaling from the insulin receptor. These results suggest insulin signaling is not so much impaired as dysregulated in AD due to factors driving downstream parts of the signaling pathway independent of the insulin receptor (e.g., oligomeric beta amyloid effects on Akt via glutamatergic NMDA receptors reported by other laboratories).Several other discoveries of the project are of interest for therapeutic research. First, the findings described above were not limited to AD cases with a history of diabetes and hence are applicable to AD in general. Second, the phosphorylation changes seen in AD often occurred to a lesser degree in MCI cases. Since MCI cases often go on to develop AD, dysregulated neuronal insulin signaling may occur early in the pathogenesis of AD. Third, the alterations in phosphorylation of insulin signaling molecules observed in MCI and AD cases were significantly and negatively correlated with indices of cognitive status of those cases, suggesting that such alterations contribute to the pathophysiology of AD dementia. Finally, while elevated serine phosphorylation of IRS-1 was found to be a striking feature of MCI and especially AD, it was not found to be a significant feature of any other form of dementia. As a result, elevated serine phosphorylation of IRS-1 may be a biomarker for an early differential diagnosis of AD if it can be detected in blood or CSF. (2) Synaptic Depletion of Dysbindin-1 in SchizophreniaThe first member of the dysbindin protein family, dysbindin-1, was discovered in 1999 as a binding partner of a- and ß-dystrobrevins belonging to the dystrophin glycoprotein complex located at muscle membranes and postsynaptic densities in the brain. The gene encoding dysbindin-1 was accordingly called dystrobrevin binding protein 1 (DTNBP1). In 2002, genetic variation in that gene was reported to be associated with schizophrenia, a finding now replicated in 14 other studies. DTNBP1 is consequently one of the best established schizophrenia risk genes. In an immunohistochemical study on postmortem human tissue, Dr. Talbot and his colleagues reported in 2004 that dysbindin-1 is normally highly enriched in synaptic fields of intrinsic glutamatergic pathways of the hippocampal formation (= hippocampus + dentate gyrus), but is depleted in the same synaptic fields of schizophrenia cases. The most profound depletion occurred in a tissue band known as the inner molecular layer of the dentate gyrus (DGiml). The same investigators reported in 2006 that dysbindin-1 in the DGiml is almost entirely associated with synaptic vesicles. Consequently, the observed dysbindin-1 depletion seen in the DGiml of schizophrenia cases must occur principally at the level of synaptic vesicles, specifically glutamatergic vesicles since these are virtually the only synaptic vesicle type in DGiml.As these and other findings suggested, synaptic depletion of dysbindin-1 seen in schizophrenia may contribute to prominent deficits in glutamatergic transmission observed in that disorder. Indeed, the 2004 publication described above noted that DGiml reductions in dysbindin-1 of schizophrenia cases were accompanied by correlated alterations in levels of vesicular glutamate transporter-1 (VGluT-1), which controls uptake of glutamate into synaptic vesicles. Dysbindin-1 may affect VGluT-1 incorporation into synaptic vesicles and other synaptic vesicle properties via its participation in a protein assembly known as BLOC-1 (= biogenesis of lysosome-related organelles complex 1), at least four of whose members are closely associated with synaptic vesicles. Other laboratories have shown that dysbindin-1 also affects dopaminergic transmission by inhibiting dopamine turnover and increasing cell surface expression of the dopamine D2 receptor, which is a major target of typical antipsychotic medications. Perhaps due to effects on glutamatergic and dopaminergic transmission, reduced gene and protein expression of dysbindin-1 is associated with cognitive deficits in humans and mice. Synaptic depletion of the dysbindin-1 in schizophrenia may thus help explain the cognitive deficits that are a core feature of the disorder. To investigate that possibility and identify dysbindin-1's molecular functions relevant to the etiology of schizophrenia, Dr. Talbot has established collaborations with investigators across the U.S., Britain, and Singapore and organized the first symposium on that topic at the Society for Neuroscience in 2004. For the same purpose, he also wrote the first comprehensive review on dysbindin-1 and its protein family for the Handbook of Neurochemistry and Molecular Neurobiology (3rd ed., in press, 2008). The dysbindin-1 project is accordingly a multi-disciplinary endeavor that includes (a) RNA and protein studies on postmortem tissues from multiple brain regions of schizophrenia and matched controls, (b) molecular, electrophysiological, and behavioral analyses on normal C57BL/6 mice and littermates with a DTNBP1 mutation resulting in loss of dysbindin-1 (i.e., sandy mice), and (c) cell culture work on cells transfected to overexpress or knockdown dysbindin-1. The project is being directed in collaboration with Dr. Steven Arnold with funding from NIMH.Select PublicationsTalbot, K. Young, R.A., Jolly-Tornetta, C., Lee, V. M.-Y., Trojanowski, J.Q., and Wolf, B.A. A frontal variant of Alzheimer's disease exhibits decreased calcium-independent phospholipase A2 activity in the prefrontal cortex. Neurochemistry International 37: 17-31, 2000.Talbot, K., Eidem, W., Tinsley, C.L., Benson, M.A., Thompson, E.W., Smith, R.J., Hahn, C.-G., Siegel, S.J., Trojanowski, J.Q., Gur, R.E., Blake, D.J., and Arnold, S.E. Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. Journal of Clinical Investigation 113: 1353-1363, 2004.Talbot, K. and Arnold, S.A. The parahippocampal region in schizophrenia. In M. Witter and F. Wouterlood (Eds.), The Parahippocampal Region, Organization and Role in Cognitive Function, pp. 297-320. New York: Oxford University Press, 2002.Arnold, S.E., Talbot, K., and Hahn, C.-G. Neurodevelopment, neuroplasticity, and new genes for schizophrenia. Progress in Brain Research 147: 319-345, 2004.Hahn, C.-G., Wang, H.-Y., Cho, D.-S., Talbot, K., Gur, R.E., Berrettini, W.H., Bakshi, K., Kamins, J., Borgmann-Winter, K.E., Siegel, S.J., and Arnold, S.E. Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nature Medicine 12: 824-828, 2006.Talbot, K., Cho, D.-S., Ong, W.-Y., Benson, M.A., Han, L.-Y., Kazi, H.A., Hahn, C.-G., Blake, D.J., and Arnold, S.E. Dysbindin-1 is a synaptic and microtubular protein that binds brain snapin. Human Molecular Genetics 15: 3041-3054, 2006.Cox, M.M., Tucker, AM, Tang J., Talbot, K., Richer, D.C., Yeh, L., and Arnold, S.E. Neurobehavioral abnormalities in the sandy mouse, a dysbindin-1 mutant, on a C57BL/6J genetic background. Genes, Brain and Behavior 7:(in press, 2008).Louneva, N., Cohen, J.W., Han, L.-Y., Talbot, K., Wilson, R.S., Bennett, D.A., Trojanowski, J.Q., and Arnold, S.E. Caspase-3 is enriched in postsynaptic densities and increased in Alzheimer's disease. American Journal of Pathology 173: (in press, 2008).Talbot, K., Ong, W.Y., Blake, D.J., Tang, J., Louneva, N., Carlson, G.C. and Arnold, S.E. Dysbindin-1 and its protein family. In D. Javitt and J. Kanorowitz (Eds.), Handbook of Neurochemistry and Molecular Neurobiology (3rd ed.), vol. 27. New York: Springer US (in press, 2008).

Skills

Specialization

Alzheimer Disease & Schizophrenia, Molecular Neuropathology