Changes in the cortical GABAergic inhibitory system in a Spinal Muscular Atrophy mouse model.

The cortical motor network excitatory-inhibitory (E/I) imbalance contributes to several neurodegenerative movement disorders. 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 motor cortex abnormalities correlating with disease severity, suggesting altered maturation and maladaptive plasticity potentially contributing to upper MN vulnerability. This raises questions about cortical involvement and highlights the need for preclinical studies to clarify underlying mechanisms, given the limited accessibility of early-stage, untreated brain tissue from SMA patients. In agreement, our previous work in SMA mice revealed upper MN vulnerability, indicating SMA pathogenesis is far more complex than classically conceived. Here, by employing a combination of imaging, molecular techniques, and electrophysiological characterization of cortical inhibitory neurotransmission, we dissected GABAergic signalling, metabolism, and interneuron function in the sensorimotor cortex and primary neuron-astrocyte co-cultures of a severe SMA mouse model. Additionally, we conducted bioinformatic analyses and biochemical assays to assess age-dependent modulation of neurotransmitter pathways and quantify key metabolites across different stages of the disease, with the overall aim of evaluating correlations between GABA levels, its precursor glutamine, the expression of synthetic enzymes (GAD65/67), and the density of Parvalbumin-positive interneurons with SMN deficiency. We unveiled a significant association between SMN deficiency and impaired density, morphology and signalling of GABAergic Parvalbumin positive interneurons in the sensorimotor cortex of late-stage SMA mice, suggesting E/I imbalance and possibly contributing to shape upper MN vulnerability. We also highlighted the pivotal role of SMN, as involved in pre-mRNA splicing, in its impact on neuronal-astrocyte interactions regulating GABA metabolism, release and reuptake. These findings underscore a role for altered motor cortical GABAergic neurotransmission in SMA progression and offer a new key perspective to achieving novel, comprehensive therapeutic approaches.