Spine loss in depression impairs dendritic signal integration in human cortical microcircuit models

Major depressive disorder (depression) is associated with altered dendritic structure and function of cortical pyramidal neurons, due to decreased inhibition from somatostatin (SST) interneurons and loss of spines and associated synapses, as indicated in postmortem human studies. Dendrites mediate signal processing through synaptic integration and nonlinear properties including backpropagating action potentials and dendritic Na⁺ spikes that enhance the neuron's computational power. However, it is currently unclear how depression-related dendritic changes impact signal integration. Here, we integrated human neuronal data of active dendritic properties and spine loss in depression into detailed computational models of human cortical microcircuits. We show that spine loss dampens signal response, worsening signal detection impairment than due to reduced SST interneuron inhibition alone. Furthermore, altered intrinsic properties due to spine loss abolished nonlinear dendritic signal integration and impaired recurrent microcircuit activity. Our study mechanistically links cellular changes in depression to impaired dendritic processing in human cortical microcircuits.