Cortical Somatostatin Innervation Follows a Unique Experience-Independent Developmental Trajectory.

Despite the critical role of inhibition in regulating developmental plasticity, there are significant gaps in our understanding of inhibitory synapse development, particularly for the vast majority of inhibitory synapses that reside on dendrites. Dendritic inhibitory synapses, canonically arising from somatostatin (SST)-expressing neurons, are challenging to detect electrophysiologically and difficult to visualize without a molecular tag. Here, we integrate a genetic synapse labeling strategy with epitope-preserving magnified analysis of proteome (eMAP), a combination of tissue expansion and clearing, to reveal the development of SST innervation in the primary visual cortex of male and female mice. Unlike excitatory innervation, which follows a deep to shallow progression and undergoes pruning, we find that SST bouton formation occurs simultaneously across all cortical layers and is not subject to a period of net pruning. SST bouton and synapse formation occur most dramatically in the days following eye opening and during the opening of the critical period for ocular dominance plasticity. Yet, despite a coincidence with these visual milestones, neither SST bouton nor synapse formation depends on visual experience. This is in contrast to excitatory and non-SST inhibitory synapses, whose development has been shown to depend heavily on visual experience. Thus, SST cortical innervation follows a unique developmental trajectory that is independent of sensory experience and is optimally timed to regulate processes that are fundamental to cortical circuit maturation.