Urban air pollutants reduce synaptic function of CA1 neurons via an NMDA/NȮ pathway in vitro.

Airborne particulate matter (PM) from urban vehicular aerosols altered glutamate receptor functions and induced glial inflammatory responses in rodent models after chronic exposure. Potential neurotoxic mechanisms were analyzed in vitro. In hippocampal slices, 2 h exposure to aqueous nanosized PM (nPM) selectively altered post-synaptic proteins in cornu ammonis area 1 (CA1) neurons: increased GluA1, GluN2A, and GluN2B, but not GluA2, GluN1, or mGlur5; increased post synaptic density 95 and spinophilin, but not synaptophysin, while dentate gyrus (DG) neurons were unresponsive. In hippocampal slices and neurons, MitoSOX red fluorescence was increased by nPM, implying free radical production. Specifically, NȮ production by slices was increased within 15 min of exposure to nPM with dose dependence, 1-10 μg/mL. Correspondingly, CA1 neurons exhibited increased nitrosylation of the GluN2A receptor and dephosphorylation of GluN2B (S1303) and of GluA1 (S831 & S845). Again, DG neurons were unresponsive to nPM. The induction of NȮ and nitrosylation were inhibited by AP5, an NMDA receptor antagonist, which also protects neurite outgrowth in vitro from inhibition by nPM. Membrane injury (EthidiumD-1 uptake) showed parallel specificity. Finally, nPM decreased evoked excitatory post-synaptic currents of CA1 neurons. These findings further document the selective impact of nPM on glutamatergic functions and identify novel responses of NMDA receptor-stimulated NȮ production and nitrosylation reactions during nPM-mediated neurotoxicity. We present three new findings of rapid hippocampal slice responses to nPM (nano-sized particulate matter from urban traffic): increased NȮ production within 15 min; nitrosylation of glutamatergic NMDA receptors; and, reduced excitatory postsynaptic currents in CA1 neurons. AP5 (NMDA receptor antagonist) blocked nPM-mediated NȮ and receptor nitrosylation. Ca(2+) influx is a likely mechanism.