Synaptic imbalance and increased inhibition impair motor function in SMA.

Movement is executed through balanced excitation-inhibition in spinal motor circuits. Short-term perturbations in one type of neurotransmission are homeostatically counteracted by the opposing type, but prolonged excitation-inhibition imbalance causes dysfunction at both single neuron and circuit levels. However, whether dysfunction in one or both types of neurotransmission leads to pathogenicity in neurodegenerative diseases characterized by select synaptic deficits is not known. Here, we used functional, morphological, and viral-mediated approaches to uncover the pathogenic contribution of unbalanced excitation-inhibition in a mouse model of spinal muscular atrophy (SMA). We show that vulnerable SMA motor circuits fail to respond homeostatically to reduced excitation and instead increase inhibition. This imposes an excessive burden on motor neurons and further restricts their recruitment. Reducing inhibition genetically or pharmacologically improves neuronal function and motor behavior in SMA mice. Thus, the disruption of excitation-inhibition homeostasis is a major maladaptive mechanism that diminishes the capacity of premotor commands to recruit motor neurons and elicit muscle contractions in SMA.