Targeted single-cell ablation uncovers network homeostasis of sound representations in mouse cortex

Sensory cortices maintain robust sensory representations despite an inevitable loss of neurons during aging and even during the prodromal stages of neurodegenerative diseases. However, the mechanisms that safeguard sensory representations and provide the cortical network with robustness against the loss of neurons are largely unknown. Here, we tested in how far the targeted elimination of functionally identified neurons affects the dynamics of sound-evoked population responses and could trigger homeostatic processes at the network level. We combined longitudinal two-photon calcium imaging of population responses evoked by a set of sound stimuli in the mouse auditory cortex and targeted single-cell laser ablation (microablation). Following several days of baseline imaging, we microablated ~30-40 cells in layer 2/3 per mouse. One day after microablation, we observed reduced sound responses as well as decorrelation toward the tuning of microablated cells in the remaining spared cells which were responsive during baseline. This was most prominent for microablation of sound responsive cells, but modest or no significant effects were observed when non-responsive cells or no cells (control group) were microablated, respectively. A group of newly responsive cells subsequently elevated the response amplitude and compensated signals to the tuning of microablated cells. Furthermore, responses in inhibitory cells were reduced, indicating an E/I imbalance after microablation. We created a representational map from the global population responses using correlation as a measure of pairwise distances. Microablation of sound-responsive neurons caused a massive collapse of the representational map that, however, was only transient and recovered in subsequent days. Together, the targeted elimination of tens of cortical neurons results in specific short-term changes in the local network dynamics, impairing its ability to form a distinct representation of the auditory world, however, in the following days the network homeostatically reinstates the representation, suggesting an underlying network-specific mechanism beyond the classical firing rate homeostasis.