Impaired attentional modulation of auditory evoked potentials in N-methyl-D-aspartate NR1 hypomorphic mice

In human neurophysiology, auditory event-related potentials (AEPs) are used to investigate cognitive processes such as selective attention. Selective attention to specific tones causes a negative enhancement of AEPs known as processing negativity (PN), which is reduced in patients with schizophrenia. The evidence suggests that impaired selective attention in these patients may partially depend on deficient N-methyl-D-aspartate receptor (NMDAR)-mediated signaling. The goal of this study was to corroborate the involvement of the NMDAR in selective attention using a mouse model. To this end, we first investigated the presence of PN-like activity in C57BL/6J mice by recording AEPs during a fear-conditioning paradigm. Two alternating trains of tones, differing in stimulus duration, were presented on 7 subsequent days. One group received a mild foot shock delivered within the presentation of one train (conditioning train) on days 3-5 (conditioning days), while controls were never shocked. The fear-conditioned group (n= 9) indeed showed a PN-like activity during conditioning days manifested as a significant positive enhancement in the AEPs to the stimuli in the conditioning train that was not observed in the controls. The same paradigm was then applied to mice with reduced expression of the NMDAR1 (NR1) subunit and to a wild-type control group (each group n= 6). The NR1 mutants showed an associative AEP enhancement, but its magnitude was significantly reduced as compared with the magnitude in wild-type mice. We conclude that electrophysiological manifestations of selective attention are observable yet of different polarity in mice and that they require intact NMDAR-mediated signaling. Thus, deficient NMDAR functioning may contribute to abnormal selective attention in schizophrenia.