Paul H. Patterson
Much of the research in this laboratory involves the study of interactions between the nervous and immune systems. Using knockout mice and over-expression in vivo with viral vectors, we are exploring the role of the neuropoietic cytokine leukemia inhibitor factor (LIF) in regulating neural stem cell proliferation and fate in the adult brain. In the context of neuroimmune interactions during fetal brain development, we are investigating a mouse model of mental illness based on the known risk factor of maternal influenza infection. Huntington's disease (HD) is another focus, where we are investigating potential therapies using intracellular expression of antibodies (intrabodies) and also manipulating NFkB activity. We are also studying the regulation of MeCP2 by IKKa, because MeCP2 mutations are responsible for Rett syndrome, which frequently involves autism symptoms.
Cytokines are diffusible, intercellular messengers that were originally studied in the immune system. Our group contributed to the discovery of a family that we termed the neuropoietic cytokines, because of their action in both the nervous and hematopoietic/immune systems. We demonstrated that one of these cytokines, LIF, can coordinate the neuronal, glial and immune reactions to injury. Using both delivery of LIF in vivo and examination of the consequences of knocking out the LIF gene in mice, we find that this cytokine has a powerful regulatory effect on the inflammatory cascade. Moreover, LIF can regulate neurogenesis and gliogenesis. LIF is a critical regulator of astrocyte and microglial activation following stroke, seizure or trauma, and this cytokine also regulates inflammatory cell infiltration, neuronal and oligodendrocyte death, gene expression, as well as adult neural stem cell renewal. These results highlight LIF as an important therapeutic target. We are currently examining the role of LIF in a chemical model of multiple sclerosis, where exogenous LIF can increase oligodendrocyte number and stimulate remyelination.
Cytokine involvement in a model for mental illness is also being investigated. This mouse model is based on findings that maternal infection can significantly increase the likelihood of schizophrenia and autism in the offspring. We are using behavioral, neuropathological, molecular, and brain imaging methods to investigate the effects of activating the maternal immune system on fetal brain development and how this leads to altered behavior in young and adult offspring. The cytokine IL-6, acting on both the placenta and fetal brain, is key in mediating the effects of maternal immune activation (MIA) on the fate of the offspring. We have new evidence that MIA alters the endogenous immune cells in the placenta, as well as lymphocyte reactions to stimulation in the adult offspring. In collaboration with the Mazmanian laboratory at Caltech, we are also examining the effects of MIA on gastrointestinal tract inflammation in the offspring.
We are utilizing intracellular antibody expression to block the toxicity of mutant huntingtin (Htt), the protein that causes HD. We produced single-chain intrabodies that bind to various domains of Htt, and these can either exacerbate or alleviate Htt toxicity in cultured cells, acute brain slices, and in Drosophila HD models. Recent findings indicate that viral delivery of one of these intrabodies in five different mouse models of HD is highly effective in ameliorating the behavioral deficits and neuropathology caused by mutant Htt in these models. We have also implicated the NFkB signaling pathway in the pathogenesis of HD, and identified several steps in this signaling cascade as potential therapeutic targets. In collaboration with the Langen laboratory at USC, using electron paramagnetic resonance spectroscopy we have obtained new structural information on the domains of mutant Htt when it forms fibrils.
Bauman, M.D., Iosif, A.M., Smith, S.E., Bregere, C., Amaral, D.G., Patterson, P.H. (2013) Activation of the maternal immune system during pregnancy alters behavioral development of Rhesus monkey offspring. Bio. Psychiatry Sep 4. pii: S0006-3223(13)00673-2. doi: 10.1016/j.biopsych.2013.06.025. [Epub ahead of print]
Garay, Paula A. and Hsiao, Elaine Y. and Patterson, Paul H. and McAllister, A. K. (2013) Maternal immune activation causes age- and region-specific changes in brain cytokines in offspring throughout development. Brain, Behavior, and Immunity, 31 . pp. 54-68. ISSN 1090-2139. Download
Khoshnan, Ali and Ou, Susan and Ko, Jan and Patterson, Paul H. (2013) Antibodies and intrabodies against Huntingtin: Production and screening of monoclonals and single-chain recombinant forms. In: Trinucleotide Repeat Protocols. Methods in Molecular Biology. No.1010. Springer , New York, pp. 231-251. ISBN 9781627034104 Download
McAllister, A. Kimberley and Patterson, Paul H. (2012) Introduction to special issue on neuroimmunology in brain development and disease. Developmental Neurobiology, 72 (10). pp. 1269-1271. ISSN 1932-8451. Download
Hsiao, Elaine Y. and Patterson, Paul H. (2012) Placental regulation of maternal-fetal interactions and brain development. Developmental Neurobiology, 72 (10). pp. 1317-1326. ISSN 1932-8451. Download
Bugg, Charles W. and Isas, J. Mario and Fischer, Torsten and Patterson, Paul H. and Langen, Ralf (2012) Structural features and domain organization of Huntingtin fibrils. Journal of Biological Chemistry, 287 (38). pp. 31739-31746. ISSN 0021-9258. Download
Hsiao, Elaine Y. and McBride, Sara W. and Chow, Janet and Mazmanian, Sarkis K. and Patterson, Paul H. (2012) Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proceedings of the National Academy of Sciences of the United States of America, 109 (31). pp. 12776-12781. ISSN 0027-8424. Download
Khoshnan, Ali and Patterson, Paul H. (2012) Elevated IKKα accelerates the differentiation of human neuronal progenitor cells and induces MeCP2-dependent BDNF expression. PLoS ONE, 7 (7). e41794. ISSN 1932-6203. Download
Malkova, Natalia V. and Yu, Collin Z. and Hsiao, Elaine Y. and Moore, Marlyn J. and Patterson, Paul H. (2012) Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain, Behavior and Immunity, 26 (4). pp. 607-616. ISSN 0889-1591 . Download
Garbett, K. A. and Hsiao, E. Y. and Kálmán, S. and Patterson, P. H. and Mirnics, K. (2012) Effects of maternal immune activation on gene expression patterns in the fetal brain. Translational Psychiatry, 2 . Art. No. e98. ISSN 2158-3188 . Download
Deverman, Benjamin E. and Patterson, Paul H. (2012) Exogenous leukemia inhibitory factor stimulates oligodendrocyte progenitor cell proliferation and enhances hippocampal remyelination. Journal of Neuroscience, 32 (6). pp. 2100-2109. ISSN 0270-6474. Download
Carlisle, Holly J. and Luong, Tinh N. and Medina-Merino, Andrew and Schenker, Leslie and Khorosheva, Eugenia and Indersmitten, Tim and Gunapala, Keith M. and Steele, Andrew D. and O'Dell, Thomas J. and Patterson, Paul H. and Kennedy, Mary B. (2011) Deletion of densin-180 results in abnormal behaviors associated with mental illness and reduces mGluR5 and DISC1 in the postsynaptic density fraction. Journal of Neuroscience, 31 (45). pp. 16194-16207. ISSN 0270-6474. Download
Khoshnan, Ali and Patterson, Paul H. (2011) The role of IkB kinase complex in the neurobiology of Huntington's disease. Neurobiology of Disease, 43 (2). pp. 305-311. ISSN 0969-9961. Download
Patterson, Paul H. (2011) Maternal infection and immune involvement in autism. Trends in Molecular Medicine, 17 (7). pp. 389-394. ISSN 1471-4914 . Download
Hsiao, Elaine Y. and Patterson, Paul H. (2011) Activation of the maternal immune system induces endocrine changes in the placenta via IL-6. Brain, Behavior, and Immunity, 25 (4). pp. 604-615. ISSN 0889-1591 . Download
Patterson, Paul H. (2011) Modeling autistic features in animals. Pediatric Research, 69 (5). 34R-40R. ISSN 0031-3998. Download
Southwell, Amber L. and Patterson, Paul H. (2011) Gene therapy in mouse models of Huntington disease. Neuroscientist , 17 (2). pp. 153-162. ISSN 1073-8584 . Download
Brown, Alan S. and Patterson, Paul H. (2011) Maternal infection and schizophrenia: Implications for prevention. Schizophrenia Bulletin, 37 (2). pp. 284-290. ISSN 0586-7614 . Download
Southwell, Amber L. and Bugg, Charles W. and Kaltenbach, Linda S. and Dunn, Denise and Butland, Stefanie and Weiss, Andreas and Paganetti, Paolo and Lo, Donald C. and Patterson, Paul H. (2011) Perturbation with intrabodies reveals that calpain cleavage Is required for degradation of Huntingtin Exon 1. PLoS ONE, 6 (1). Art. No. e16676. ISSN 1932-6203. Download