Acute Inhibition of NMDA Receptor Function by Bisphenol A and Bisphenol F in Adult Rat Brain

Bisphenol A (BPA), a widely used industrial chemical, is a bioactive environmental contaminant with established neurodevelopmental toxicity. Yet, its effects on the mature brain remain poorly understood. Given the central role of N-methyl-D-aspartate receptors (NMDARs) in synaptic plasticity and cognition, we examined whether acute BPA exposure disrupts NMDAR function and spatial cognition in adult rats. Whole-cell patch-clamp recordings from hippocampal neurons and HEK293 cells expressing recombinant receptors showed that BPA (100 µM) potently and reversibly inhibited NMDAR-mediated currents (~90%) in a dose-dependent, subunit- and voltage-independent manner, consistent with allosteric modulation. The structural analogue bisphenol F (BPF) produced similar, though slightly weaker (~75%), inhibition. In vivo , a single BPA administration (400 µg/kg, i.p.) impaired spatial precision, evidenced by a reduced number of crossings over the target location during the post-reversal probe trial in the Morris water maze. These findings demonstrate that BPA acutely suppresses NMDAR signaling and disrupts NMDAR-dependent cognition in adulthood. The comparable effects of BPF on NMDAR highlight that current “BPA-free” substitutes may not represent safer alternatives. • BPA and BPF directly impair postsynaptic NMDA receptor function in primary hippocampal neuronal cultures. • GluN2A-containing NMDA receptors show greater susceptibility to BPA and BPF than GluN2B-containing receptors. • Acute BPA exposure reduces spatial memory precision during reversal learning in the Morris water maze.