NMDAR-mediated shift of neuronal gain across the cortical hierarchy

Neuronal gain is a critical feature of neuronal information processing, reflecting a cells excitability in response to presynaptic inputs. Evidence from spine counts in non-human primates suggests that the number of presynaptic inputs increases across the cortical hierarchy. Therefore, understanding the regulation of the neuronal gain can yield important insights into different integration strategies across the cortex. Along with the increasing spine counts, there is further evidence for a similar increase in NMDA-receptor-mediated currents. Here, we show, using detailed simulations of a thick-tufted layer 5 pyramidal neuron, that the amount of current mediated through NMDA receptors (NMDARs) strongly affects the neuronal gain function with balanced presynaptic inputs. Without NMDA, postsynaptic activity quickly saturates and declines with increasing inputs. However, with NMDARs, the gain of postsynaptic activity shifts into higher input regimes, enabling integration of dense inputs. We show that, with NMDARs, a significant fraction of postsynaptic activity arises from feedback between the voltage dependence of NMDARs and voltage-gated sodium channels. Lastly, we show, using a network model, that NMDAR knockout in single cells has differential effects on postsynaptic activity depending on network size (a proxy for cortical hierarchy). Thus, we propose that an NMDA gradient across the cortical hierarchy may be necessary to maintain excitability amid increasing presynaptic input.