Bisphenol-A (BPA, 4, 4′-isopropylidene-2-diphenol), a synthetic xenoestrogen that widely used in the production of polycarbonate plastics, has been reported to impair hippocampal development and function. Our previous study has shown that BPA exposure impairs Sprague-Dawley (SD) male hippocampal dendritic spine outgrowth. In this study, the sex-effect of chronic BPA exposure on spatial memory in SD male and female rats and the related synaptic mechanism were further investigated. We found that chronic BPA exposure impaired spatial memory in both SD male and female rats, suggesting a dysfunction of hippocampus without gender-specific effect. Further investigation indicated that BPA exposure causes significant impairment of dendrite and spine structure, manifested as decreased dendritic complexity, dendritic spine density and percentage of mushroom shaped spines in hippocampal CA1 and dentate gyrus (DG) neurons. Furthermore, a significant reduction in Arc expression was detected upon BPA exposure. Strikingly, BPA exposure significantly increased the mIPSC amplitude without altering the mEPSC amplitude or frequency, accompanied by increased GABAARβ2/3 on postsynaptic membrane in cultured CA1 neurons. In summary, our study indicated that Arc, together with the increased surface GABAARβ2/3, contributed to BPA induced spatial memory deficits, providing a novel molecular basis for BPA achieved brain impairment.

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Homeostatic synaptic plasticity (HSP) helps to stabilize the neuronal network activity, which is essential for optimal information coding. Synaptic scaling is a form of homeostatic plasticity that stabilizes neuronal firing in response to activity blockade. Lead (Pb) is a ubiquitous environmental neuro-toxicant and can impair the input-specific Hebbian type synaptic plasticity, but whether Pb exerts effects in HSP remains unknown. We previously reported that blocking L-type calcium channel induces synaptic scaling, which stimulates the synthesis of all-trans retinoic acid (RA) and the expression of GluA2-lacking α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. Given Pb is a potent blocker of calcium channel, we hypothesized Pb may participate in synaptic scaling accompanied by RA synthesis and AMPA receptor trafficking. In this study, cultured hippocampal neurons were treated with Pb (1 μM 5 min, 15 min, 4 h, 24 h, and 10 μM 24 h) alone or in combination with tetrodotoxin (TTX, 1 μM, 24 h). The results showed that Pb alone, either at 1 μM or 10 μM, cannot induce synaptic scaling. But Pb participated in synaptic scaling when concurrent with TTX (10 μM Pb + 1 μM TTX, 24 h). Further results showed that surface heteromeric GluA1 and GluA2 AMPA receptors were increased in TTX+ Pb-induced synaptic scaling. In addition, RA was proved not to participate in TTX+ Pb-mediated synaptic scaling. Taken together, our work supported that TTX+ Pb could induce synaptic scaling and enhance synaptic accumulation of AMPAR GluA1 and GluA2 during synaptic up scaling. Our study would help for elucidation of the Pb-induced neuronal network instability mechanism.

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