40 Hz gamma synchrony: association cortices are more vulnerable than primary auditory cortex to NMDA blockade

The 40 Hz auditory steady response (ASSR) is an EEG measure of local gamma neural synchrony that is evoked by the repeated presentation of a 40 Hz click train. While the principal cortical generators of this response appear to be bilateral primary auditory cortices as they show the largest phase locking and evoked power, other regions across the cortical mantle synchronize, including the prefrontal cortex (PFC) that receives input from the primary auditory cortex and is involved in higher order cognitive functions. In schizophrenia, PFC function is compromised and it is hypothesized that NMDA-dependent neurotransmission is involved. Indeed, in rodents, NMDA antagonists reliably disrupt set shifting, a working memory task linked to PFC function. It is however not known if NMDA antagonism would disrupt the40 Hz ASSR. In the following study, we equipped separate groups of female SD rats with epidural electrode targeting the PFC (1.5 mm anterior and 1 mm lateral to bregma) or the primary auditory cortex (5 mm caudal, 7.25 mm lateral and 3.5 mm ventral to bregma). Two epidural screw electrodes on cerebellum served as ground and reference. After recovery from surgery, and acclimation, rats were pretreated with a modest dose of the NMDA antagonist MK801 (0.05 mg/kg) or saline (2 ml/kg,sc) in a cross-over design, tethered to EEG cables and EEG was amplified and acquired (Signal 7.0; CED1401 Micro 3). Trains of square waves (~ 1 ms duration; 40/s)were generated and played through the house speakers at ~ 50 dB SPL. EEG was acquired as 5 s sweeps while a 40 Hz click train played between 1-2 s, of each sweep;50 trials were recorded from each subject, 30 min post-treatment. Post-vehicle, robust EEG entrainment was noted in both the temporal cortex as well as the PFC. As expected, the EEG signal and phase-locking from the temporal cortex was notably larger compared to the PFC. Nevertheless, both regions showed clear 40 Hz entrainment to click trains. However, MK801 effect on the 40 Hz ASSR was disparate across the two regions. The temporal lead showed a significant increase in intertrial coherence (ITC) of the 40 Hz ASSR (P=0.03; paired t-test), while background gamma (35-45 Hz) power also increased (p=0.027). Evoked power showed a trend towards an increase (p<0.1). In contrast, ITC was strongly disrupted in the frontal lead (p=0.005) and evoked power showed a trend towards reduction (p=0.059),while background gamma was unaffected. These results indicate that neural synchrony in higher order cortices like the PFC are more vulnerable to NMDA antagonist-mediated disruption, as compared to the primary auditory cortex.