Konrad Talbot, PhD
Assistant Research Professor in Neurobiology
Department of Psychiatry Bio
Dr. 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.
While 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 light and electron microscopy, his primary technical skills are in various anatomical and molecular methods revealing the structure, input-output organization, and/or chemical composition of neuronal networks that mediate behavior. Dr. Talbot's research group has optimized these methods for postmortem tissue, permitting detection in human tissue of small protein levels, fractionation of synaptosomes into pre- and post-synaptic elements, and quantification of phosphorylated forms of proteins in intact tissue sections. Building on his graduate training in animal behavior, Dr. Talbot helped establish 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 symposium chair at the American College of Neuropsychopharmacology and the Society for Neuroscience.
The 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 noted earlier: synaptic depletion of dysbindin-1 in schizophrenia and altered neuronal insulin signaling in AD and. Dr. Talbot is leading research projects investigating both those phenomena as described below.
Schizophrenia is a severe psychiatric disorder that comes to clinical attention with onset of the first psychotic symptoms, which usually occurs between ages 20 and 35. It is estimated that about 50 million people alive today are afflicted by the disorder or will be in their lifetimes. The diagnostic features are dominated by what are called positive symptoms defining psychosis (delusions, hallucinations, and thought disorders) and by negative symptoms reflecting absence of normal behaviors such as inability to experience pleasure, blunted emotional expression, poverty of speech, lack of initiative, and reduced social interactions . In addition to diagnostic symptoms are cognitive deficits that are also core features of the disorder.
While current drug treatments often alleviate the positive symptoms, they are ineffective against the negative symptoms and only partially effective against the cognitive deficits of the disorder. Yet these two features have a far greater impact on ability to function than the positive symptoms . Effective treatments for the negative symptoms and cognitive deficits of schizophrenia are thus urgently needed. The need is urgent not only because of the suffering endured by the patients and their families, but because of the large health care costs and lost income caused by the disorder each year (estimated at £6.7 billion in the U.K. and $62.7 billion in the U.S.A.).
Since 2002, many new drug targets for treatment of schizophrenia have emerged with discovery of many genes associated with risk for the disorder. Among the top risk genes is DTNBP1, which has been associated with schizophrenia in 18 studies on populations across the globe . One or more of the schizophrenia-related alleles of DTNBP1 are found to be associated with some of the patients’ positive and negative symptoms, as well as with several of their cognitive deficits. Some of these alleles are also associated with patient responsiveness to typical and atypical antipsychotic medications.
Dysbindin-1 Pathology in Schizophrenia
The protein encoded by DTNBP1 (the dystrobrevin binding protein 1 gene) was the first member of the dysbindin protein family to be discovered and is thus best known as dysbindin-1. Reported in 2001, this protein is ubiquitously expressed in neurons but is concentrated only in synaptic fields where glutamate, dopamine, and/or GABA act as transmitters . Based on postmortem research conducted in the laboratory of Professor Steven E. Arnold at UPenn, Dr. Talbot and his colleagues discovered that schizophrenia cases have reduced levels of dysbindin-1 in a brain area dysfunctional in such cases, namely the hippocampal formation (HF, see Fig. 1) . This consists of the hippocampus proper (fields CA1-CA3), dentate gyrus, and subiculum. Reduced dysbindin-1 was found in both sets of schizophrenia cases studied: middle-aged cases of the Stanley Foundation and elderly cases of the UPenn. Compared to normal individuals, 73% of the younger cases and 93% of the older ones showed dysbindin-1 reductions in axon terminals of HF neurons that use glutamate as a transmitter. These terminals allow direct communication among the principal neurons of the HF and help mediate the cognitive functions of this brain area. Later work on an animal model of dysbind-1 loss (sandy mice) confirmed that such loss impairs cognitive function (see below).
The UPenn Dysbindin-1 Project
With funding from the National Institute of Mental Health, Drs. Talbot and Arnold initiated a multidisciplinary study on the neurobiology of synaptic dysbindin-1 in schizophrenia and in sandy mice, which have a deletion mutation in DTNBP1 that leads to dysbindin-1 loss (see Fig. 2). The project is an international collaboration with other investigators at UPenn (Natalia Louneva and Gregory C. Carlson), Cardiff University in the U.K. (Derek J. Blake and Nigel M. Williams), and the National University of Singapore (Wei-Yi Ong). The project has access to postmortem brains from schizophrenia cases who participated in a longitudinal study of the disorder conducted by UPenn .
The dysbindin-1 project has made several discoveries in recent years. Among the more important findings are the following. (1) Reduced synaptic dysbindin-1 is common not only in the HF of schizophrenia cases, but in other brain areas of such cases (i.e., prefrontal  and auditory cortices). Reduction in the latter area may promote auditory hallucinations. (2) Where tested thus far, these reductions are not due to decreased dysbindin-1 gene expression, suggesting other factors such as altered protein synthesis and metabolism . (3) One such factor is the E3 ubiquitin ligase TRIM32, a newly discovered dysbindin-1 binding partner, which appears to regulate levels of at least one dysbindin-1 isoform . (4) Dysbindin-1 is associated with synaptic vesicles and binds another protein (snapin) associated with those vesicles , which helps explain how dysbindin-1 promotes glutamate release . (5) Dysbindin-1 loss in sandy mice is associated cognitive deficits found in schizophrenia . Other labs report similar observations in sandy mice and find that such mice show a negative symptom of schizophrenia (social withdrawal) .
Future directions of the Dysbindin-1 Project
There are two long-term goals of the dysbindin-1 project. One is discovering means of restoring normal levels of this protein in schizophrenia. The other is discovering means of compensating for the functional consequences of reduced dysbindin-1. This requires discovering the molecular mechanisms by which synaptic levels of dysbindin-1 are regulated (e.g., TRIM32-mediated degradation of the protein) and by which reductions of the protein promotes symptoms and cognitive deficits in schizophrenia (e.g., snapin-related modulation of synaptic glutamate release). Such work holds the promise of translating basic research on dysbindin-1 into pharmacological treatment for as yet refractory clinical features of schizophrenia.
(2) Alzheimer Disease
Over the last decade, an increasing number of studies have shown (a) that type 2 diabetes is a risk factor for AD , (b) that gene and protein expression of the upstream molecules in insulin signaling pathways are reduced in AD brains , and (3) that the activated forms of those molecules are also reduced in such brains [13, 14]. The latter two findings indicate 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 affected early in AD (i.e., hippocampal field CA1) where damage impairs memory. This project, funded by the Alzheimer Disease Association, has been conducted in collaboration with Drs. Steven Arnold and John Trojanowski here at UPenn and with Drs. David Bennett and Robert Wilson at Rush University in Chicago.
The UPenn Insulin Signaling in AD Project
This studies postmortem tissue from two sets of cases. One is a set of elderly controls and AD cases collected by the Center for Neurodegenerative Disease Research at UPenn. The other is a set of normal elderly, mild cognitively impaired (MCI), and AD cases collected by the Religious Order Study run by Rush University in Chicago. Using quantitative immunohistochemistry with phospho-specific antibodies, Dr. Talbot demonstrated chronic changes in phosphorylation of both upstream and downstream insulin signaling molecules in hippocampal CA1 neurons in both sets of cases . Such changes were different in upstream versus downstream molecules of the insulin signaling pathway. The insulin receptor in AD was less tyrosine phosphorylated, indicating chronically decreased receptor activation. Yet phosphorylation of all downstream molecules in the insulin signaling (e.g., Akt and GSK-3) pathway 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 that are independent of the insulin receptor (e.g., oligomeric beta amyloid effects on Akt via glutamatergic NMDA receptors reported by other labs).
Several other discoveries of the project are of interest for translational 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.
 Lindenmayer, JP et al. (2007) Schizophrenia: measurements of psychopathology. Psychiatric Clinics of North America, 30: 339-363.
 Kurtz, MM (2006) Symptoms versus neurocognitive skills as correlates of everyday functioning in severe mental illness. Expert Reviews in Neurotherapeutics, 6: 47-56.
 Talbot, K et al. (2009) Dysbindin-1 and its protein family with special attention to the potential role of dysbindin-1 in neuronal functions and the pathophysiology of schizophrenia. In D Javitt and J Kantorowitz (Eds.), Handbook of Neurochemistry and Molecular Neurobiology (3rd ed.), vol. 27. New York: Springer US (in press).
 Talbot, K et al. (2004) "Dysbindin is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia." Journal of Clinical Investigation, 113: 1353-1363.
 Arnold, SE et al. (1995) Prospective clinicopathologic studies of schizophrenia: accrual and assessment of patients. American Journal of Psychiatry, 152: 731-737.
 Tang, J et al. (2009) Dysbindin-1 in dorsolateral prefrontal cortex of schizophrenia cases is reduced in an isoform-specific manner unrelated to dysbindin-1 mRNA expression. Human Molecular Genetics, 18 (in press).
 Louneva, N. et al. (2009) Decreased TRIM32 in schizophrenia may alter synaptic regulation of dysbindin-1C and AMPA receptor recycling in the hippocampal formation. (Abstract 155.10 of presentation at the Society for Neuroscience Annual Meeting, Chicago, IL)
 Talbot, K et al. (2006) Dysbindin-1 is a synaptic and microtubular protein that binds brain snapin. Human Molecular Genetics, 15, 3041-3054.
 Cox M et al. (2009) Neurobehavioral abnormalities in the sandy mouse, a dysbindin-1 mutant, on a C57BL/6J background. Genes, Brain and Behavior 8, 390-397.
 Hattori, S. et al. (2008) Behavioral abnormalities and dopamine reductions in sdy mutant mice with a deletion in Dtnbp1, a susceptibility gene for schizophrenia. Biochemical and Biophysical Research Communications, 373: 298-302; Feng, Y.-Q. et al. (2008) Dysbindin deficiency in sandy mice causes reduction of snapin and displays behaviors related to schizophrenia. Schizophrenia Research, 106: 218-228.
 Haan, MN (2006) Therapy insight: type 2 diabetes mellitus and the risk of late-onset Alzheimer's disease. Nature Clinical Practice, 2: 159-166.
 Steen, E. et al. (2005) Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease - is this type 3 diabetes? Journal of Alzheimer’s Disease, 7: 63-80.
 Talbot, K. et al. (2007) Multiple levels of the insulin signaling pathway in hippocampal field CA1 are compromised in mild cognitive impairment (MCI) and Alzheimer Disease (AD). (Abstract 223.15 of presentation at Society for Neuroscience Annual Meeting, San Diego, CA)
 Moloney, AM et al. (2009) Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer's disease indicate possible resistance to IGF-1 and insulin signaling. Neurobiology of Aging, 30 (in press).
- Alzheimer's Disease/Dementia
- Behavioral Genetics
- Learning and Memory
- Molecular and Cellular Neuropathology
- Molecular Genetics
- Signal Transduction
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