SMN DEFICIENCY IMPAIRS CORTICAL GABAERGIC INHIBITION IN A MOUSE MODEL OF SPINAL MUSCULAR ATROPHY

Spinal Muscular Atrophy (SMA) is a neuromuscular disease due to lack of Survival Motor Neuron (SMN) protein, characterized by lower motor neuron (MN) degeneration and muscle atrophy. Increasing evidence of cortical morphofunctional abnormalities in SMA patients highlights maladaptive plasticity, making preclinical models crucial to define cortex (CRTX) involvement. Here, we dissected inhibitory GABAergic signaling and interneuron function within the sensorimotor CRTX (SM-CRTX) of SMNdelta7 mice, combining ex vivo analyses with neuron-astrocyte co-cultures. Morphological and molecular analyses revealed late-disease alterations of SMA SM-CRTX inhibitory circuits, including reduction of GABA⁺ neurons (−38%), with pronounced loss in layer V, indicating selective vulnerability of output-layer inhibitory circuits rather than pan-cortical degeneration. Consistently, GABA synthesis was impaired due to reduced GAD65/67 expression (−25%), with marked alterations in morphology and density of parvalbumin⁺ interneurons, particularly in motor CRTX layer V (−33%), where concomitant loss of inhibitory synapses (−50%) led to reduced inhibitory control of pyramidal neurons, as confirmed by electrophysiological recordings. Seeking causes of reduced inhibition, we identified a key role for altered neuron-astrocyte crosstalk in GABA handling, driven by SMN deficiency-induced astrocytic sodium-dependent transporter expression changes (SNAT5 −45%; GAT3 +29%), leading to GABA accumulation in astrocytes and reduced neuronal availability. SMN restoration induced by Nusinersen, an SMN-splicing therapy for SMA, partially rescued neuron-astrocyte GABAergic metabolism in SMA cortical cultures by normalizing astrocytic transporter expression and enhancing GABA levels. Overall, these findings identify SMN deficiency-induced cortical GABAergic dysfunction as a circuit-level mechanism contributing to SMA pathophysiology, advancing disease understanding and therapy design.