MORPHOLOGICAL AND SYNAPTIC CHANGES OF THE CORTICAL GABAERGIC INHIBITORY SYSTEM IN SPINAL MUSCULAR ATROPHY
Bibliographic record
Abstract
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. Moreover, evidence shows motor cortex (CRTX) morphofunctional abnormalities in SMA patients, suggesting altered maturation and maladaptive plasticity. Given limited access to patient samples, preclinical models are mandatory to clarify motor cortical involvement and underlying mechanisms in SMA pathogenesis. Building on our previous observation of upper MN vulnerability in SMA mice, we dissected cortical inhibitory GABAergic signalling, metabolism, and interneuron (IN) function in the sensorimotor (SM) CRTX and in primary neuron-astrocyte co-cultures from a severe SMA mouse model, compared to WT controls. Bioinformatic and biochemical analyses revealed stage-specific alterations in GABAergic pathways and metabolite profiles, particularly at late stage (P12), indicating a critical window of cortical network vulnerability. Imaging and molecular studies showed GABA+ neuron loss (-38%) and impaired GABA synthesis (GAD65/67). Moreover, confocal analysis revealed marked morphological alterations of parvalbumin (PV)+ INs in the SM CRTX of SMA mice, characterized by smaller somas and reduced dendritic dendritic complexity compared to controls. To determine whether these changes affected specific cortical layers, we quantified PV+ IN distribution and found a pronounced reduction in layer 5 of the motor CRTX (M1: -33.1%; S1: -25.7%). Consistently, the density of inhibitory synapses, assessed by gephyrin/GAD puncta, was markedly decreased in the SMA motor CRTX, particularly in layer 5 compared to WT controls (≤50%). Electrophysiological characterizations further confirmed decreased inhibitory neurotransmission onto layer 5 pyramidal neurons. Subsequent analyses showed that SMN loss impairs GABA release and reuptake by altering astrocytic transporter expression (SNAT5: -45%; GAT3: +29%), leading to reduced neuronal GABA and its accumulation in astrocytes. This imbalance leads to cortical GABAergic dysfunction, contributing to SMA pathology and highlighting SMN’s critical role in neurotransmitter regulation. Our data support a mechanistic model in which SMN deficiency impairs cortical GABAergic networks, expanding our understanding of cortical mechanisms in SMA and providing a framework for cortical-targeted therapeutic strategies.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".