Spinal Muscular Atrophy (SMA) is a neuromuscular disease due to the lack of Survival Motor Neuron (SMN) protein, characterized by lower motor neuron (MN) degeneration and muscle atrophy. However, evidence shows that SMA patients display brain abnormalities correlating with disease severity, suggesting altered maturation and maladaptive plasticity potentially contributing to cortical alterations. Our previous work in SMA mice revealed upper MN vulnerability, indicating SMA pathogenesis is far more complex than classically conceived. We have shown that SMN deficiency influences cortical layering and cytoarchitecture during corticogenesis. This developmental misplacement may represent an early event that predisposes projection neurons to subsequent degeneration. Not all cortical neurons are equally affected: corticospinal and then callosal projection neurons emerge as particularly vulnerable populations, displaying both structural and survival deficits in response to SMN reduction. More recently, by employing a combination of imaging, molecular techniques, and electrophysiological characterization of cortical inhibitory neurotransmission, we dissected GABAergic signaling, metabolism, and interneuron function in the sensorimotor cortex.