Sex difference in stress-induced enhancement of hippocampal CA1 long-term depression during puberty.

Females and males react differently to stress. Our previous studies revealed that acute stress facilitates the induction of long-term depression (LTD) in hippocampal CA1 region. However, it remains unknown whether sex difference exists in the effect of stress on LTD. Using an acute unpredictable and inescapable restraint-tailshock stress paradigm, we report here that hippocampal slices from stressed male rats expressed larger LTD by low-frequency stimulation (LFS) than controls, whereas such effect was not observed in female rats during puberty. The facilitatory effect of stress on LTD was prevented when animals were submitted to bilateral adrenalectomy. However, no sex difference in the magnitudes of LTD induced by direct application of N-methy-D-aspartate or a combination of LFS with the glutamate uptake inhibitor D,L-threo-β-benzyloxyaspartate was observed in slices from naive rats. Female rats exhibited significantly higher basal but not stress-evoked levels of plasma corticosterone than male rats. In addition, the expression levels of glucocorticoid receptors in hippocampal CA1 region were significantly lower in female than male rats. Moreover, female rats showed less responsiveness to stress- or dexamethasone-induced suppression of glutamate uptake in hippocampal synaptosomal preparations than male rats. Importantly, female rats that were masculinized with testosterone at birth responded to stress like male rats did, demonstrating an enhancement of LTD. In contrast, ovariectomized female rats failed to restore the ability of stress to facilitate LTD. These results reveal an obvious sex difference in stress-induced modification of hippocampal synaptic plasticity, which depends on organizational effect of testosterone during early development.