The neurologic basis of depression and response to antidepressant treatment remain uncertain. Recent evidence suggests that the brain derived neurotrophic factor (BDNF) is increased by administration of various classes of antidepressant treatments and BDNF infusion into the brain has antidepressant effects in animal models. Furthermore, BDNF's role in acute regulation of synaptic transmission and synaptic plasticity in the hippocampus and other areas, implicates a role in learning and memory paradigms. The proposed studies will examine the role of BDNF in the adult brain in depression and response to antidepressant treatments. These studies will also screen BDNF deficient mice for deficits in two learning and memory paradigms. We hypothesize that mice lacking BDNF in the brain will exhibit increased susceptibility stress effects in animal models of depression and that these mice will be less susceptible to beneficial effects of anitidepressant therapy. We further hypothesize that mice lacking BDNF in the brain will exhibit deficits in learning and memory paradigms. Finally, we will examine the role of BDNF in support of monoaminergic and serotonergic projections in the adult brain. These studies will enhance our understanding of the pathophysiology of depression and mechanisms of antidepressant action. This knowledge may lead to new therapeutic targets in depression. Experiments examining the role of BDNF in spatial and emotional learning and memory will further our understanding of how neurotrophic factors can influence learning and memory and may lead to new therapeutic considerations in clinical disorders of memory such as Alzheimer's disease. To date, studies examining the role of BDNF in behavioral paradigms have been difficult due to the early postnatal lethality and sensory abnormalities of constitutive BDNF knockout mice. Our approach will be to make use of brain-directed, inducible BNDF knockout mice that have been generated in the Nestler laboratory. This system avoids developmental and peripheral effects of traditional knockout approaches. We also propose to make use of focal injection of Cre-expressing AAV vectors into flox-BDNF mice to assess the specific brain subregions involved with greater temporal specificity. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08MH065975-04
Application #
7036492
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Wynne, Debra K
Project Start
2003-04-01
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
4
Fiscal Year
2006
Total Cost
$172,995
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Psychiatry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Blundell, Jacqueline; Blaiss, Cory A; Lagace, Diane C et al. (2011) Block of glucocorticoid synthesis during re-activation inhibits extinction of an established fear memory. Neurobiol Learn Mem 95:453-60
Netzer, William J; Powell, Craig; Nong, Yi et al. (2010) Lowering beta-amyloid levels rescues learning and memory in a Down syndrome mouse model. PLoS One 5:e10943
Blundell, Jacqueline; Kaeser, Pascal S; Südhof, Thomas C et al. (2010) RIM1alpha and interacting proteins involved in presynaptic plasticity mediate prepulse inhibition and additional behaviors linked to schizophrenia. J Neurosci 30:5326-33
Blundell, Jacqueline; Blaiss, Cory A; Etherton, Mark R et al. (2010) Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior. J Neurosci 30:2115-29
Blundell, J; Tabuchi, K; Bolliger, M F et al. (2009) Increased anxiety-like behavior in mice lacking the inhibitory synapse cell adhesion molecule neuroligin 2. Genes Brain Behav 8:114-26
Zhang, Chen; Milunsky, Jeff M; Newton, Stephanie et al. (2009) A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export. J Neurosci 29:10843-54
Zhou, Jing; Blundell, Jacqueline; Ogawa, Shiori et al. (2009) Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice. J Neurosci 29:1773-83
Hawasli, Ammar H; Koovakkattu, Della; Hayashi, Kanehiro et al. (2009) Regulation of hippocampal and behavioral excitability by cyclin-dependent kinase 5. PLoS One 4:e5808
Etherton, Mark R; Blaiss, Cory A; Powell, Craig M et al. (2009) Mouse neurexin-1alpha deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments. Proc Natl Acad Sci U S A 106:17998-8003
Blundell, Jacqueline; Hoang, Chau V; Potts, Bryan et al. (2008) Motor coordination deficits in mice lacking RGS9. Brain Res 1190:78-85

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