Perinatal bisphenols combined exposure caused working memory impairment by disturbing the ventral hippocampus-medial prefrontal cortex circuit

Bisphenols (BPs), ubiquitous in food packaging, medical, and personal care products, are pervasive environmental contaminants. As bisphenol A (BPA) is increasingly replaced by its alternatives, the risk of mixed exposure and its impact on critical cognitive functions, such as working memory, remains a pressing but understudied concern. Here, we modeled developmental exposure to BPA and a bisphenol mixture (BPmix, BPA: BPS: BPF = 9:0.5:0.5) by administering the compounds to dams via drinking water during gestation and lactation. Behavioral analyses revealed that BPA and BPmix exposure significantly reduced the working memory of mouse pups in both the T-maze and novel object recognition tests compared with controls. In vivo electrophysiological investigation revealed a critical functional deficit in the medial prefrontal cortex (mPFC), with BPA-exposed pups displaying markedly reduced local theta (θ) and gamma (γ) oscillation power during the choice phase of the T-maze test. This was accompanied by weakened θ/γ cross-regional coupling within the ventral hippocampus (vHPC)-mPFC circuit of BPA-exposed pups. This network dyssynchrony was linked to impaired synaptic plasticity, evidenced by suppressed long-term potentiation (LTP) at the vHPC-mPFC synapse. Patch-clamp recordings showed a lower amplitude of excitatory postsynaptic currents without a change in frequency. Consistently, this postsynaptic deficit was accompanied with a significant decrease in spine density of pyramidal neurons and excitatory receptor expression in the mPFC. Together, our findings delineate a comprehensive circuit- and synaptic-level mechanism underlying the working memory deficits caused by developmental BPs exposure. • Perinatal BPs exposure induces working memory deficits in offspring of mice. • BPs-induced memory dysfunction correlates with decreased local activity in the mPFC. • BPs disrupts θ-γ oscillation coupling in the vHPC-mPFC circuit. • Synaptic plasticity impairment in the mPFC is linked to BPs-induced cognitive dysfunction.