Our research interests focus on the molecular and cellular basis of neural plasticity as it pertains to psychiatric disorders. We are utilizing molecular, cellular, behavioral, biochemical and electrophysiological approaches to elucidate how specific genes may contribute to psychiatric disorders. We are specifically focusing on better understanding Depression & Rett Syndrome/Autism.
A major goal in the laboratory is to identify and understand the role of neurotrophic growth factors in the adult brain. Alterations in these factors and their intracellular signaling pathways have been suggested to play an important role in many psychiatric illnesses including depression and in the therapeutic action of antidepressants. A second project is concerned with elucidating the role of Methyl-CpG-binding protein (MeCP2) in the central nervous system. Mutations in the MeCP2 gene cause the autism spectrum disorder, Rett Syndrome (RTT).
Project 1: Antidepressant drugs are commonly prescribed for the treatment of depression although their mechanisms of action are not well understood. Recent studies suggest that antidepressants exert their effect in part by upregulating the levels of brain-derived neurotrophic factor (BDNF) in specific brain regions, most notably the hippocampus. We are investigating the role of hippocampal BDNF in animal models of depression and in antidepressant action. We have developed several lines of transgenic animals in which BDNF is ?knocked out? in a regionally and temporally specific manner in the hippocampus. We have demonstrated that loss of BDNF in acute stress paradigms does not necessarily contribute to a more ?depressed-like? phenotype, however, these animals no longer respond to antidepressant drugs. We are examining these mice in several other paradigms to see whether chronic stress paradigms, such as with social defeat, produces a more depressed phenotype in the BDNF knockout mice and also the requirement of BDNF for more chronic antidepressant action. We have also used a viral mediated approach to delete BDNF in subregions of the hippocampus and found that the selective deletion in the dentate gyrus, but not other subregions, results in an attenuated response to antidepressants thereby localizing the BDNF mediated effect on antidepressant action. We are also studying intracellular signaling pathways, and target genes, by which BDNF may be contributing to antidepressant actions. This work is funded by grants from the National Institute of Mental Health (NIMH) and the National Alliance for Research on Schizophrenia and Depression (NARSAD). Project 2: A second major area of research in the lab is to analyze the role of the Methyl-CpG-binding protein (MeCP2) in the pervasive developmental disorder, Rett Syndrome (RTT). Rett Syndrome is a neurodevelopmental disorder that accounts for one of the leading causes of mental retardation and autistic behavior in females. The MeCP2 gene encodes a chromosome binding protein that binds to methylated cytosines in the mammalian genome and then recruiting histone deacetylases to form a complex to repress gene expression. Mutations in this gene, which are believed to result in loss of function, are found in over 95% of all RTT patients and several Autism patients. We have generated conditional MeCP2 mice and shown that these animals recapitulate many aspects of RTT including the increased anxiety, motor impairments and autistic-like behavior similar to that observed in RTT patients. We have also been analyzing how the loss of MeCP2 contributes to impairments in synaptic function as well as potential genes that may be dysregulated in the disease process. We are also currently examining the role of DNA methylation as well as histone deacetylases in mediating effects on synaptic plasticity. This work is funded by the National Alliance for Autism Research, The Once Upon a Time Foundation, the Rett Syndrome Research Foundation, and the National Institute of Mental Health (NIMH).
RESEARCH INTERESTS
Development of Animal Models for Psychiatric Diseases
Role of Growth Factors in Depression
Elucidating the Role of MeCP2 in Mediating Autistic-like Behavior (autism)
Role of Transcriptional Repression in Neurons
RECENT PUBLICATIONS
Gemelli T, Berton O, Nelson E, Perroti LI, Jaenisch R, Monteggia LM, "Postnatal loss of MeCP2 in the forebrain is sufficient to mediate behavioral aspects of Rett Syndrome in mice" Biol Psychiatry, Epub Sept 28 2005
Monteggia LM, Luikart B, Barrot M, Nef S, Parada LF, Nestler EJ, "BDNF Conditional Knockouts Show Gender Differences in Depression Related Behaviors." Biological Psychiatry, 61(2):187-197, 2007
Hensler JG, Advani T, Monteggia LM, "Regulation of 5-HT1A receptor function in inducible BDNF knock-out mice following administration of corticosterone." Biological Psychiatry, Epub March 2 2007
Lippmann M, Bress A, Nemeroff CB, Plotsky PM, Monteggia LM, "Long Term Behavioral and Molecular Alterations Associated with Maternal Separation in Rats." European Journal of Neuroscience, 25(10):3091-3098, 2007
Mahgoub MA, Sara Y, Kavalali ET, Monteggia LM, "Reciprocal interaction of activity and 5-HT in regulation of CRE-dependent gene expression." J Pharmacol Exp Ther, 317(1):88-96, 2006
SIGNIFICANT PUBLICATIONS
Berton, O, McClung CA, Dileone RJ, Krishnan V, Renthal W, Russo SJ, Graham D, Tsankova NM, Bolanos CA, Rios M, Monteggia LM, Self DW, Nestler EJ, "Essential Role of BDNF in the Mesolimbic Dopamine Pathway in Social Defeat Stress" Science, 311:864-868, 2006
Monteggia LM, Barrot M, Powell C, Berton O, Galanis V, Nagy A, Greene RW, Nestler EJ, "Essential Role of BDNF in Adult Hippocampal Function and Depression" Proc Natl Acad Sci, 101(29):10827-10832, 2004
Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM, "Neurobiology of Depression" Neuron, 34(1):13-25, 2002
Nelson E, Kavalali ET, Monteggia LM, "MeCP2-dependent transcriptional repression regulates excitatory neurotransmission" Current Biology, 16:710-716, 2006
Nelson ED, Kavalali ET, Monteggia LM, "Activity-dependent suppression of miniatureneurotransmission through the regulation of DNA methylation" J Neurosci, 28(2)::395-406, 2008
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