Recent studies have suggested that brain-derived neurotrophic factor (BDNF) plays a role in depression and antidepressant-like behavioral effects. BDNF expression is decreased in the hippocampus, a brain region implicated in the pathophysiology of depression, by exposure to stress, a factor implicated in depression in some individuals. Conversely, multiple classes of antidepressants, as well as electrocpnvulsive therapy (ECT), increase BDNF expression in the hippocampus in a time course consistent with the therapeutic action of these drugs. BDNF, the most prevalent growth factor in the brain, can then exert alterations in neuronal plasticity through specific signaling pathways. However, a clear link between the role of endogenous BDNF and 'depression-like' behavior and in the behavioral responses to antidepressant drugs remains unclear. The main goal of this project is to investigate, 1) whether the loss of BDNF produces changes in 'depressive-like' behavior and antidepressant responses and, 2) whether chronic antidepressant treatment exerts effects on synaptic plasticity in a BDNF dependent manner. 1 major aim is to examine whether the loss of endogenous BDNF in the hippocampus of 3 complementary genetic mouse approaches produces a 'depressive' phenotype in animal models of depression. We also will examine whether these mice display attenuated behavioral responses to antidepressants.
A second aim will focus on the role of BDNF in exerting downstream effects following antidepressant treatment. We have demonstrated an increase in the phosphorylation of the glutamate receptor subunit, N-methyl-D-aspartate 1 (NR1) on a protein kinase C (PKC) site following chronic antidepressant treatment. Previous data has shown that BDNF may regulate NR1 phosphorylation, which then potentiates NMDA receptor function. Changes in NMDA receptor function could mediate long-term consequences in synaptic plasticity. We will pursue the increase in NR1 phosphorylation by chronic antidepressant action to examine whether this upregulation is mediated via alterations in BDNF. Together, the proposed molecular, cellular, and behavioral studies promise to advance our understanding of the role of BDNF that chronic antidepressants induce in the hippocampus.
| Horvath, Patricia M; Monteggia, Lisa M (2018) MeCP2 as an Activator of Gene Expression. Trends Neurosci 41:72-74 |
| Monteggia, Lisa M; Lin, Pei-Yi; Adachi, Megumi et al. (2018) Behavioral Analysis of SNAP-25 and Synaptobrevin-2 Haploinsufficiency in Mice. Neuroscience : |
| Crawford, Devon C; Ramirez, Denise M O; Trauterman, Brent et al. (2017) Selective molecular impairment of spontaneous neurotransmission modulates synaptic efficacy. Nat Commun 8:14436 |
| Horvath, Patricia M; Kavalali, Ege T; Monteggia, Lisa M (2017) CRISPR/Cas9 system-mediated impairment of synaptobrevin/VAMP function in postmitotic hippocampal neurons. J Neurosci Methods 278:57-64 |
| Adachi, Megumi; Autry, Anita E; Mahgoub, Melissa et al. (2017) TrkB Signaling in Dorsal Raphe Nucleus is Essential for Antidepressant Efficacy and Normal Aggression Behavior. Neuropsychopharmacology 42:886-894 |
| Ramirez, Denise M O; Crawford, Devon C; Chanaday, Natali L et al. (2017) Loss of Doc2-Dependent Spontaneous Neurotransmission Augments Glutamatergic Synaptic Strength. J Neurosci 37:6224-6230 |
| Björkholm, Carl; Monteggia, Lisa M (2016) BDNF - a key transducer of antidepressant effects. Neuropharmacology 102:72-9 |
| Monteggia, Lisa M (2016) Toward Better Animal Models for Molecular Psychiatry. Biol Psychiatry 79:2-3 |
| Kavalali, Ege T; Monteggia, Lisa M (2015) How does ketamine elicit a rapid antidepressant response? Curr Opin Pharmacol 20:35-9 |
| Monteggia, Lisa M; Zarate Jr, Carlos (2015) Antidepressant actions of ketamine: from molecular mechanisms to clinical practice. Curr Opin Neurobiol 30:139-43 |
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