Bruce K. Krueger, PhD

The principal research interests of my laboratory are the cellular and molecular mechanisms of brain development that underlie pathological cognitive behavior in autism and other neurodevelopmental disorders. 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 trimester of pregnancy. Neither the causes nor the underlying mechanisms of autism are known. Variants of multiple neuronal genes have been linked to the disorder, however, in most cases, there is no known causative mechanism; moreover, exposure of pregnant women to the anti-epileptic drug, valproic acid (VPA) or other environmental factors such as pollutants and pesticides has been shown to dramatically increase the incidence of autism in their offspring. In addition, rodents exposed to VPA in utero display autistic-like symptoms as adults. These findings suggest that both genes and the environment play a role in causing autism.

Initially, our research focused on the role of brain-derived neurotrophic factor (BDNF) in the effects of VPA on the fetal brain; 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 connectivity defects in neuronal circuits underlying behavior. This research investigated the mechanisms by which VPA increases BDNF expression in the fetal brain. Because VPA is an inhibitor of histone deacetylases, we predicted that epigenetic mechanisms underlie the stimulation of BDNF expression by VPA. Indeed, increased production of Bdnf transcripts in the fetal mouse brain is primarily due to lysine acetylation of histones at multiple regulatory sites across the Bdnf gene modulated by methylation of histone 3 lysine 4 trimethylation.

I have recently completed a study of the effects of VPA on the fetal mouse brain transcriptome. Genes dysregulated by VPA include modulators of critical steps in brain development such as neurogenesis, neuronal fate determination, axon and dendrite growth, and synaptogenesis. Future research will be aimed at determining the extent to which disruption of one or more of these developmental steps is the proximal cause of autistic-like behavior.

We are now turning to the hypothesis that the combination of genetic predisposition and in utero environmental toxin is a critical factor in neurodevelopmental disorders. We hypothesize that fetal exposure to an environmental toxin (e.g., VPA, pesticides) in genetically susceptible individuals will result in autism when either genes or the environment alone will not. This hypothesis has not been systematically tested. Such interactions could explain the variable severity of autistic symptoms, i.e., among individuals with a similar genetic predisposition, we predict that those that are exposed to toxic environmental factors in utero will be more likely to develop severe symptoms. Future studies will focus on analogous gene-environment interactions in Down syndrome (DS, trisomy 21), which shares multiple potentially pathogenic genes with autism.

• RNAseq; snRNAseq
• 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
• Measurement of cell survival; assays of apoptosis (pyknosis, TUNEL)
• Computer assisted calcium imaging
• Mechanisms of cell signaling
• Confocal microscopy
• Animal behavior (mice)

I would be happy to discuss opportunities for GPILS graduate students in the Neuroscience and Molecular Medicine programs to undertake laboratory rotations with the possibility of conducting their dissertation research in my laboratory.

Former Graduate Students

• Tarik F. Haydar (Ph.D. 1997) Professor and Director of Neuroscience, Children's National Medical Center, Washington, DC
• 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) Professor, UMB School of Nursing (sdorsey@umaryland.edu)
• Peter D. Murray (Ph.D., 2008) Program Director, National Center for Complementary and Integrative Health, NIH. (pmurr002@gmail.com)
• Melissa A. Konopko (Ph.D, 2017) Scientific Product Manager, Elixir hub at EMBL's European Bioinformatics Institute and Technical Programme Manager, Global Alliance for Genomics and Health, Cambridge UK.

Former Postdoctoral Fellows

• Tami J. Kingsbury, Ph.D., Scientific Review Officer, Division of Basic and Integrative Biological Sciences, NIH (tami.kingsbury@nih.gov )
• Luis E. F. Almeida, M.D., Ph.D. Senior Scientist, Intramural Program, NIH (falcassa@hotmail.com)