Our research focuses on a better understanding of the molecular and cellular mechanisms that underlie psychiatric disorders. Our work to date covers two critical areas of psychiatric neuroscience. First, we are investigating the role of neurotrophins, in particular brain‑derived neurotrophic factor (BDNF), and their receptors in adult brain function using conditional and inducible, cell type specific knockout mice. Our work has established a critical role for BDNF in determining antidepressant efficacy as well as certain aspects of depressive like behavior. Specifically, our research has demonstrated that BDNF selectively in the hippocampus dentate gyrus is necessary to mediate antidepressant responses in rodent models. We have also showed that gender differences observed in depressed humans, with females being more vulnerable, can be recapitulated in these BDNF deficit models in mice. More recently, we have been investigating the mechanism underlying fast acting antidepressant efficacy. Here, we could demonstrate that ketamine mediated NMDA receptor blockade at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase resulting in a reduction of eEF2 phosphorylation and de-suppression of BDNF translation that is necessary for rapid behavioral antidepressant responses.
Our second area of research aims to elucidate the pathophysiology of autistic‑like behavior and neuronal dysfunction using mouse models of Rett Syndrome, a pervasive developmental disorder that accounts for one of the leading causes of autism and mental retardation in females. In the last four years, our work has identified key synaptic deficiencies associated with Rett Syndrome and defined the specific brain regions that give rise to symptoms associated with the disease in mouse models. Furthermore, this work also lead to a thorough investigation of epigenetic factors that regulate synapse maturation and synaptic efficacy in the central nervous system. Epigenetic regulation of synapse function carries wide ranging implications that go beyond the etiology of Rett Syndrome to mechanisms underlying other autism spectrum disorders as well as other psychiatric disorders.
Within the laboratory we combine advanced molecular, cellular, behavioral, and electrophysiological studies to probe these critical scientific questions at multiple steps, and thereby establish causal links among these diverse levels of analysis. These types of multi‑based approaches are critical for understanding the brain, and will hopefully yield insight into then study of depression as well as the field of autism spectrum disorders.
Primary Research Publications
Depression Project1. Autry A. E., Adachi M., Nosyreva E, Na ES, Los MF, Cheng P, Kavalali, ET, Monteggia LM (2011) NMDA Receptor Blockade at Rest Triggers Rapid Behavioural Antidepressant Responses. Nature 275(7354):91-95.
2. Autry AE, Adachi M, Cheng P, Monteggia LM (2009) Gender Specific Impact of BDNF signaling on Stress-Induced Depression-Like Behavior. Biol Psychiatry, 66(1):84-90.
3. Adachi M, Barrot M, Autry A, Theobald D, Monteggia LM (2008) Selective loss of brain-derived neurotrophic factor in the dentate gyrus attenuates antidepressant efficacy. Biol Psychiatry 63:642-649.
4. Monteggia LM, Luikart B, Barrot M, Nef S, Parada LF, Nestler EJ. (2007) BDNF Conditional Knockouts Show Gender Differences in Depression Related Behaviors. Biol Psychiatry, 61(2):187-197.
5 Mahgoub MA, Sara Y, Kavalali ET, Monteggia LM (2006) Reciprocal interaction of activity and 5-HT in regulation of CRE-dependent gene expression. J Pharmacol Exp Ther 317(1):88-96.
6. Monteggia LM, Barrot M, Powell C, Berton O, Galanis V, Nagy A, Greene RW, Nestler EJ (2004) Essential Role of BDNF in Adult Hippocampal Function and Depression. Proc Natl Acad Sci, 101(29):10827-10832.
Epigenetic Project1. Nelson ED, Kavalali ET, Monteggia LM (2011) Selective Impact of MeCP2 and associated Histone
Deacetylases on the Dynamics of Evoked Excitatory Neurotransmission. J Neurophysiol 106(1):193-201.
2. Adachi M, Autry AE, Covington HE 3rd, Monteggia LM (2009) MeCP2-mediated Transcription Repression in the basolateral amygdala may underlie heightened anxiety in a mouse model of Rett Syndrome. J Neurosci 29(13):4218-4227.
3. Akhtar MW, Raingo J, Nelson ED, Montgomery RL, Olson EN, Kavalali ET, Monteggia LM (2009) Histone deacetylases 1 and 2 form a developmental switch that controls excitatory synapse maturation and function. J Neurosci 29(25):8288-97.
4. Nelson ED, Kavalali ET, Monteggia LM (2008) Activity-dependent suppression of miniature
neurotransmission through the regulation of DNA methylation. J Neurosci 28(2):395-406.
5. Gemelli T, Berton O, Nelson E, Perroti LI, Jaenisch R, Monteggia LM (2006) Postnatal loss
of MeCP2 in the forebrain is sufficient to mediate behavioral aspects of Rett Syndrome in mice.
Biol Psychiatry, 59(5):468-476.
6. Nelson E, Kavalali ET, Monteggia LM (2006) MeCP2-dependent transcriptional repression regulates excitatory neurotransmission. Current Biology 16:710-716.