Effects of estradiol on learned helplessness and associated remodeling of hippocampal spine synapses in female rats.
BACKGROUND
Despite the fact that women are twice as likely to develop depression as men, our understanding of depression neurobiology in female subjects is limited. We have recently reported in male rats that development of helpless behavior is associated with a severe loss of hippocampal spine synapses, which is reversed by treatment with the antidepressant desipramine. Considering that estradiol has a hippocampal synaptogenic effect similar to those of antidepressants, the presence of estradiol during the female reproductive life might influence behavioral and synaptic responses to stress and depression.


METHODS
With electron microscopic stereology, we analyzed hippocampal spine synapses in association with helpless behavior in ovariectomized female rats (n = 70), under different conditions of estradiol exposure.


RESULTS
Stress induced an acute and persistent loss of hippocampal spine synapses, whereas subchronic treatment with desipramine reversed the stress-induced synaptic loss. Estradiol supplementation given either before stress or before escape testing of nonstressed animals increased the number of hippocampal spine synapses. Correlation analysis demonstrated a statistically significant negative correlation between the severity of helpless behavior and hippocampal spine synapse numbers.


CONCLUSIONS
These findings suggest that hippocampal spine synapse remodeling might be a critical factor underlying learned helplessness and, possibly, the neurobiology of depression.
Hajszan
Tibor
T
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA. tibor.hajszan@yale.edu
Szigeti-Buck
Klara
K
Sallam
Nermin L
NL
Bober
Jeremy
J
Parducz
Arpad
A
Maclusky
Neil J
NJ
Leranth
Csaba
C
Duman
Ronald S
RS
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D056547:CA1 Region, Hippocampal / Q000166:cytology*; D049229:Dendritic Spines / Q000187:drug effects* / Q000648:ultrastructure; D004195:Disease Models, Animal; D004597:Electroshock / Q000009:adverse effects; D004924:Escape Reaction / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006380:Helplessness, Learned; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D010052:Ovariectomy / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D012044:Regression Analysis; D013238:Stereotaxic Techniques; D013315:Stress, Psychological / Q000150:complications / Q000209:etiology / Q000473:pathology; D013569:Synapses / Q000187:drug effects / Q000648:ultrastructure; D013997:Time Factors
D004967:Estrogens; D004958:Estradiol