Age-dependent increased sag amplitude in human pyramidal neurons dampens baseline cortical activity.

Aging involves various neurobiological changes, although their effect on brain function in humans remains poorly understood. The growing availability of human neuronal and circuit data provides opportunities for uncovering age-dependent changes of brain networks and for constraining models to predict consequences on brain activity. Here we found increased sag voltage amplitude in human middle temporal gyrus layer 5 pyramidal neurons from older subjects and captured this effect in biophysical models of younger and older pyramidal neurons. We used these models to simulate detailed layer 5 microcircuits and found lower baseline firing in older pyramidal neuron microcircuits, with minimal effect on response. We then validated the predicted reduced baseline firing using extracellular multielectrode recordings from human brain slices of different ages. Our results thus report changes in human pyramidal neuron input integration properties and provide fundamental insights into the neuronal mechanisms of altered cortical excitability and resting-state activity in human aging.