Prolonged developmental programming of somatostatin neurons defines adolescent remodeling of the prelimbic, but not...

Higher order association cortices like the prefrontal cortex (PFC) mature over a longer developmental window than sensory cortices, but whether genetically defined interneuron populations follow this region-wide delayed trajectory remains unclear. We compared the postnatal development of somatostatin-expressing interneurons in a higher-order cortical region (prelimbic cortex; PLC) and a sensory cortical region (somatosensory barrel cortex; S1BF) across adolescence using complementary structural, electrophysiological, and circuit analyses. We found that the maturation of SST neurons within these two cortical regions differs across time. S1BF SST neurons exhibited relatively linear maturation, whereas PLC SST neurons underwent continued dendritic remodeling, nonlinear intrinsic maturation, and age-dependent refinement of inhibitory output onto pyramidal neurons. Multivariate analyses likewise supported a more linear developmental trajectory in S1BF and a more prolonged, heterogeneous trajectory in PLC. This suggests divergent maturation of the PLC and S1BF and supports a broader, longer window of critical cellular plasticity in the PLC than in sensory cortices. Together, this reflects an extended developmental program at the level of a genetically defined inhibitory cell type. Because SST neurons are positioned to regulate pyramidal neuron output via control of dendritic integration, their delayed maturation is a crucial reflection of overall circuit function. These findings provide a cellular framework for the prolonged plasticity and developmental vulnerability known to be characteristic of adolescent prelimbic cortex.

Within the brain, higher order association cortex remains plastic long after sensory cortex has matured, but the cellular basis for this prolonged developmental window has remained unknown. We find that developmental timing is encoded within genetically defined microcircuits. Prelimbic somatostatin circuits continue to remodel after sensory somatostatin circuits have largely stabilized through changes in cell shape, action potential firing dynamics, and inhibitory signaling. This work points to a specific prelimbic inhibitory cell type that matures more slowly, and less linearly, than its counterparts in other brain regions, and may help explain why prelimbic circuits remain vulnerable during adolescence, representing a biological substrate for extended adolescent remodeling in prelimbic cortex, and potentially the overall extensive flexibility, but also cognitive susceptibility, seen during adolescence.