Depression is one of the most common neurological disorders in the United States, affecting approximately 17% of the population with a clear sex difference. According to a current hypothesis, efficacy of antidepressant drugs depends on increased hippocampal neurogenesis, elicited after prolonged antidepressant medication. Since rapid changes in mood state that occur, e.g., at the onset of individual depressive episodes cannot be reconciled with slowly evolving neurogenetic alterations, an argument has been raised recently that antidepressant treatment might also involve a more rapid cellular plasticity mechanism that affects the integrity of the hippocampal neuronal circuitry. We have discovered that treatment of ovariectomized female rats with fluoxetine for 5 days elicits a robust increase in the density of dendritic spine synapses in the CA 1 hippocampal area and dentate gyrus, while spine synapse density increases of similar magnitude in the CAS area can be observed only after 14-day treatment. These spine synapse changes in CA 1 and dentate gyrus occur long before the first indications of increased dentate gyrus neurogenesis. Based on these data, we hypothesize that the mechanism of antidepressant action involves the induction of spine synapse formation in the hippocampus, leading to the restoration of the hippocampal neuronal circuitry and behavioral improvement. Since this same neuronal circuit is also a major target of gonadal steroid action, this mechanism may not only be associated with rapid changes in mood state, but also may provide an explanation for the sex and age differences in rates of depression and responses to antidepressant treatment. To test this hypothesis, we propose a combination of morphological and behavioral experiments in the rat that will investigate (a) the sequence and behavioral correlates of fluoxetine-induced hippocampal spine synapse changes; (b) the hippocampal synaptogenetic potential of several classes of antidepressants; (c) the neuronal substrates of the hippocampal synaptogenetic effect of several antidepressants; and (d) the possible sex and age differences in fluoxetine-induced hippocampal spine synapse changes. The experiments proposed in this application represent the first step in our effort to understand the role and significance of hippocampal synaptic remodeling in the neurobiology of depression and antidepressant therapy. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH074021-03
Application #
7373629
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Nadler, Laurie S
Project Start
2006-02-01
Project End
2010-01-31
Budget Start
2008-02-01
Budget End
2010-01-31
Support Year
3
Fiscal Year
2008
Total Cost
$277,827
Indirect Cost
Name
Yale University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Baka, Judith; Csakvari, Eszter; Huzian, Orsolya et al. (2017) Stress induces equivalent remodeling of hippocampal spine synapses in a simulated postpartum environment and in a female rat model of major depression. Neuroscience 343:384-397
Miettinen, Riitta; Hajszan, Tibor; Riedel, Anett et al. (2012) Estimation of the total number of hippocampal CA1 pyramidal neurons: new methodology applied to helpless rats. J Neurosci Methods 205:130-8
Hajszan, Tibor; Szigeti-Buck, Klara; Sallam, Nermin L et al. (2010) Effects of estradiol on learned helplessness and associated remodeling of hippocampal spine synapses in female rats. Biol Psychiatry 67:168-74
Hajszan, Tibor; Leranth, Csaba (2010) Bisphenol A interferes with synaptic remodeling. Front Neuroendocrinol 31:519-30
Hajszan, Tibor; Dow, Antonia; Warner-Schmidt, Jennifer L et al. (2009) Remodeling of hippocampal spine synapses in the rat learned helplessness model of depression. Biol Psychiatry 65:392-400
Leranth, Csaba; Szigeti-Buck, Klara; Maclusky, Neil J et al. (2008) Bisphenol A prevents the synaptogenic response to testosterone in the brain of adult male rats. Endocrinology 149:988-94
Leranth, Csaba; Hajszan, Tibor; Szigeti-Buck, Klara et al. (2008) Bisphenol A prevents the synaptogenic response to estradiol in hippocampus and prefrontal cortex of ovariectomized nonhuman primates. Proc Natl Acad Sci U S A 105:14187-91
Hajszan, Tibor; MacLusky, Neil J; Leranth, Csaba (2008) Role of androgens and the androgen receptor in remodeling of spine synapses in limbic brain areas. Horm Behav 53:638-46
Hajszan, Tibor; Milner, Teresa A; Leranth, Csaba (2007) Sex steroids and the dentate gyrus. Prog Brain Res 163:399-415
Leranth, Csaba; Hajszan, Tibor (2007) Extrinsic afferent systems to the dentate gyrus. Prog Brain Res 163:63-84

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