Mechanisms regulating the frequency of inhibition-based gamma oscillations in primate prefrontal and parietal cortices

In primates, the dorsolateral prefrontal (DLPFC) and posterior parietal (PPC) cortices are critical nodes in the network mediating cognitive functions including attention and working memory. Notably, during working memory tasks, gamma oscillations, usually prominent in layer 3 (L3), are induced in both DLPFC and PPC but exhibit higher frequency in DLPFC. These oscillation frequency differences might be crucial for working memory function, but the mechanisms producing different oscillation frequencies in monkey DLPFC and PPC remain poorly understood. To investigate the basis of the DLPFC-PPC differences in oscillation frequency we studied GABAAR-mediated inhibition, which plays a crucial role in gamma oscillation production, in L3 pyramidal neurons (L3 PNs) from the rhesus monkey DLPFC or PPC. Recordings of GABAAR-mediated synaptic currents from L3 PNs, while suggesting a contribution to network synchronization in both areas, revealed no DLPFC-PPC differences in the strength or kinetics of GABAAR-mediated inhibition. Likewise, the expression of GABAAR genes in L3 PNs did not differ between regions. In the absence of differences in inhibition, DLPFC L3 PNs showed greater dendritic spine density and higher expression of AMPAR and NMDAR subunit genes relative to PPC L3 PNs, suggesting that the excitatory synaptic drive onto L3 PNs could be stronger in the DLPFC. Simulations in computational models of the cortical microcircuit showed that, with constant synaptic inhibition, increasing the strength of recurrent excitatory synaptic drive increased the network oscillation frequency. Hence, the DLPFC-PPC differences in gamma oscillation frequency could depend on stronger recurrent excitation in the DLPFC relative to PPC. Significance statement Gamma oscillations may contribute to the neural substrate of working memory and exhibit a higher frequency in the prefrontal (DLPFC) than parietal (PPC) areas of primate cortex. To investigate the basis of these oscillation frequency differences which may be crucial for working memory encoding, we studied GABAAR-mediated inhibition on L3 pyramidal neurons (L3 PNs) from rhesus monkey DLPFC or PPC. Our data revealed no DLPFC-PPC differences in GABAAR-mediated inhibition but showed greater dendritic spine density in DLPFC L3 PNs, suggesting stronger excitatory synaptic drive. Simulations in computational network models showed that stronger recurrent excitatory synaptic drive increased the network oscillation frequency, suggesting that the higher oscillation frequency could depend on stronger recurrent excitation in the DLPFC relative to PPC. ### Competing Interest Statement David A. Lewis currently receives investigator-initiated research support from Merck. All other authors declare no conflict of interest.