EARLY DISRUPTION OF MORPHOLOGICAL AND FUNCTIONAL DEVELOPMENT IN LAYER 2/3 PYRAMIDAL NEURONS OF 16P11.2 DELETION MICE

Proper functional and morphological maturation of cortical neurons is essential for building cortical circuits, and disruptions in these early processes are strongly implicated in neurodevelopmental disorders (NDDs). A key unresolved issue is developmental timing: early cell-autonomous defects may be transient or later masked by compensation mechanisms, yet still trigger downstream circuit dysfunction - creating a critical window for disease pathogenesis. Here, we investigated early cortical neuronal developmental processes in the mouse model of the NDD-associated 16p11.2 deletion syndrome. We performed electrophysiological and morphological characterization of primary somatosensory cortex Layer 2/3 pyramidal neurons at postnatal days 7 (P7), P14, and P28. Whole-cell patch-clamp recordings and morphological reconstructions revealed that P7 mutant neurons exhibit developmental defects, including reduced capacitance, smaller surface area, fewer dendrites, and reduced excitability. Remarkably, by P14, these features largely recover to wild-type levels; however, action potential dynamics remain significantly altered, suggesting persistent ion channel maturation deficits. Ongoing work extends these analyses to later developmental stages (P28) and incorporates analysis of single neuron dynamic gain by noise injections as well as Layer2/3 intra-connectivity analysis using single unit recordings, to link early single-cell abnormalities and circuit-level outcomes. These findings indicate that the 16p11.2 deletion causes early and evolving alterations in intrinsic neuronal properties - initial defects in growth and excitability followed by partial structural recovery but enduring biophysical impairments.