I received my Ph.D. from the Department of Molecular Biophysics and Biochemistry at Yale University in 1975, and sub-sequently conducted research as a postdoctoral fellow with Paul Greengard (Yale University School of Medicine) and Mordecai Blaustein (Washington University School of Medicine). I came to the University of Maryland School of Medicine as an Assistant Professor of Physiology in 1979, and was promoted to Professor in 1990. I also have a secondary appointment as Professor of Psychiatry. At the present time my laboratory is funded by the National Institute of Child Health and Development (NIH). I have been the recipient of Alfred P. Sloan Foundation, Guggenheim, and Fogarty Inter-national fellowships. During the 1991-92 academic year, I was on sabbatical leave in the laboratory of Martin Raff (University College London) studying programmed cell death (apoptosis) during brain development. My past research focused on the molecular structure and function of ion channels in excitable membranes and I continue to be co-coursemaster of "Ion Channels", offered annually to second-year Ph.D. students. I have been Director of Graduate Education for the Program in Neuroscience since 2011.
BDNF in the developing, adult and aging brain
The principal research interests of my laboratory are the cellular and molecular mechanisms that underlie brain development and cognitive behavior. Much of our work has focused on the mechanism of action of the neurotrophin, brain-derived neurotrophic factor (BDNF), acting via its receptor, trkB. During development, BDNF promotes neuron production and survival and regulates the growth of axons and the specificity of synaptic connections. In the mature brain, BDNF not only maintains neuron survival but also influences cognitive function by modulating synaptic plasticity. Some studies suggest that depletion of BDNF levels in the aging brain may contribute to cognitive decline. Our research has identified novel regulatory elements in the gene encoding trkB that enable intracellular Ca2+ to modulate the expression of trkB and, consequently, neuronal sensitivity to BDNF (Kingsbury et al., 2003; 2007a). We have also discovered a novel mechanism by which neurotransmitters that act via cAMP (such as dopamine) regulate the expression of CREB-dependent genes such as BDNF (Almeida et al., 2009); this mechanism operates in neurons but not glial cells (Murray et al., 2009). More recently, we have obtained evidence that abnormal BDNF levels during fetal brain development may cause autism (see below).
Developmental mechanisms of autism
Recent research has revealed that while the characteristic behavioral symptoms of autism emerge during the second year of life, these behaviors probably reflect errors in brain development occurring much earlier, probably during the first tri-mester of pregnancy. Neither the causes nor the underlying mechanisms of autism are known. Many studies have linked polymorphisms in multiple neuronal genes to the disorder, however, in most cases, there is no known causative factor. In addition, exposure of pregnant women to certain drugs and environmental factors such as pollutants and pesticides has been shown to dramatically increase the incidence of autism in their offspring. These findings suggest that both genes and the environment play a role in causing autism and that the cognitive deficits can be attributed to errors in fetal brain development.
Dr. Elizabeth Powell (Associate Professor of Anatomy and Neurobiology) and I recently received a 5-year (R01) research grant from the NIH to study the mechanisms underlying the induction of autism by fetal exposure to valproic acid (VPA) a widely-used anti-epileptic and mood elevating drug. Women who take VPA during the first trimester are about 10-times more likely to give birth to autistic children. Our research is focused on the role of BDNF in this process; in preliminary studies we found that administration of VPA to pregnant mice resulted in a large increase in BDNF in the fetal brain. An abnormal spike in BDNF during a critical developmental window of vulnerability is predicted to profoundly alter the development of the cerebral cortex and hippocampus, leading to permanent wiring defects in neuronal circuits underlying behavior. Our research project will investigate the mechanisms by which VPA increases BDNF expression in the fetal brain and the potential role of the increased BDNF in causing abnormal production, differentiation and survival of exci-tatory and inhibitory neurons resulting in autistic behavior. This research will utilize state-of-the-art molecular, cellular and behavioral methods.
Future studies will focus directly on gene-environment interactions in autism. We hypothesize that fetal exposure to an environmental factor in genetically susceptible individuals will result in autism when either factor alone will not. This hy-pothesis has not been systematically tested. Such interactions could explain the variable severity of autistic symptoms, i.e., among individuals with similar genetic makeups, those that are exposed to environmental factors in utero will be more likely to develop autism.
Lab Techniques and Equipment
- Recombinant DNA technology
- Measurement of mRNA and DNA by quantitative real-time PCR
- Measurement of protein and RNA expression by in situ hybridization, northern and western blotting
- Epigenetic regulation of gene expression by DNA methylation and covalent chromatin modifications
- Developmental neuroanatomy; immunohistochemistry; neural pathway mapping
- Cell culture (neurons, astrocytes, organotypic brain slices)
- Measurement of cell survival; assays of apoptosis (pyknosis, TUNEL)
- Computer assisted calcium imaging
- Mechanisms of cell signaling
- Confocal microscopy
- Animal behavior (mice)
Opportunities for Graduate Student Rotations & Dissertation Research:
I would be happy to discuss opportunities for GPILS graduate students in the Neuroscience and Molecular Medicine pro-grams to undertake laboratory rotations with the possibility of conducting their dissertation research in my laboratory.
Former Graduate Students & Postdoctoral Fellows:
Former Graduate Students
- Ai-Wu Cheng (Ph.D., 2000) Staff Scientist, Gerontology Research Center, National Institute on Aging, Baltimore, MD (ChengAi@grc.nia.nih.gov)
- Susan G. Dorsey (Ph.D., 2001) Associate Professor and Associate Dean for Research, UMB School of Nursing (sdorsey@ son.umaryland.edu)
- Peter D. Murray (Ph.D., 2008) science writer, Singularity Hub (email@example.com)
Former Postdoctoral Fellows
- Tami J. Kingsbury, Ph.D., Assistant Professor, UMB Center for Stem Cell Biology and Regenerative Medicine (tking001@ umaryland.edu)
- Luis E.F. Almeida, M.D., Ph.D. Staff Scientist, Children’s National Medical Center, Washington DC. (falcassa @hotmail.com)
Dorsey, S.G., Bambrick, L.L., Krueger, B.K. (2002) Failure of BDNF-dependent neuron survival in mouse trisomy 16. Journal of Neuroscience 22:2571-2578.
Bambrick, L.L., Yarowsky, P.J., Krueger, B.K.(2003) Altered astrocyte calcium homeostasis and proliferation in theTs65Dn mouse, a model of Down syndrome. Journal of Neuroscience Research 73:89-94.
Kingsbury, T.J., Murray, P.D., Bambrick, L.L., Krueger, B.K.(2003) Ca2+-dependent regulation of trkB expression in neurons. Journal of Biological Chemistry 278:40744-40748.
Cheng, A., Haydar, T.F., Yarowsky, P.J., Krueger, B.K. (2004) Concurrent generation of subplate and cortical plate neurons in developing trisomy 16 mouse cortex. Developmental Neuroscience 26(2-4):255-265.
Dorsey, S.G., Renn, C.L., Carim-Todd, L., Barrick, C.A., Bambrick, L.L., Krueger, B.K., Ward, C.W., Tessarollo, L. (2006) In vivo restoration of physiological levels of truncated TrkB.T1 receptor rescues neuronal cell death in a trisomic mouse model. Neuron 51:1-8.
Kingsbury T.J., B.K. Krueger. (2007a) Ca2+, CREB and Krüppel: A novel KLF7-binding element in mouse and human TRKB promoters required for neuron-specific, activity-dependent transcription. Molecular Cellular Neuroscience 35:447-455. PMCID: PMC2042965
Kingsbury, T.J., Bambrick, L.L., Roby, C.D., Krueger, B.K. (2007b) Calcineurin activity is required for depolarization-induced, CREB-dependent gene transcription in cortical neurons. J. Neurochemistry 103:761-770.
Almeida, L.E.F., Murray, P.D., Zielke, H.R., Roby, C.D., Kingsbury, T.J., Krueger, B.K. (2009) Autocrine activation of neuronal NMDA receptors by aspartate mediates dopamine- and cAMP-induced CREB-dependent gene transcription. Journal of Neuroscience 29:12702-12710. PMCID: PMC2804479
Murray, P.D., Kingsbury, T.J., Krueger. B.K. (2009) Failure of Ca2+-activated, CREB-dependent transcription in astrocytes. Glia 57:828-834. PMCID: PMC2669848
Almeida, L.E.F., Roby, C.D., Krueger, B.K. Increased BDNF expression in fetal brain following in utero exposure to valproic acid: implications for autism. Molecular and Cellular Neuroscience, in revision.
Almeida, L.E.F., Roby, C.D., Krueger, B.K. Aspartate mediates dopamine-induced CREB-dependent gene transcription: effects of a specific aspartate release inhibitor, submitted.