Loose coupling between Ca²⁺ channels and release sensors as a synaptic correlate of higher-order brain function

In the mature neocortex, functionally distinct areas are built by the same archetypes of neurons, but depending on the area, these neurons and their synapses are engaged in very different functions, ranging from lower-order processing of sensory information to higher-order associations and cognitive functions. We found significant differences in the functional presynaptic nanoarchitectures of the same types of pyramidal neuron synapses, depending on whether they are located in the prefrontal cortex (PFC) or in the primary somatosensory cortex (S1) of mice. Mature synapses in PFC operated with loose microdomain coupling, as opposed to tight nanodomain coupling in S1. These differences were associated with significant differences in synaptic timing, efficacy, and plasticity between areas. Our data suggest that the mature neocortex uses tuning of synaptic topographies to specialize seemingly identical types of neurons for their required function. They suggest that microdomain coupling in pyramidal neuron synapses could be a presynaptic structure-function correlate of higher-order neocortical functions.