Loss of connectivity between spinal V1 inhibitory inter-neurons and motor neurons is found early in disease in the SOD1G93A ALS mice. Such changes in premotor inputs can contribute to homeostatic imbalance of vulnerable motor neurons. Here, we show, for the first time, that stabilization of V1 synapses by overexpression of the Extended Synap-totagmin 1 presynaptic organizer increases motor neuron survival and ameliorates motor phenotypes, demonstrating that interneurons can be a potential target to attenuate ALS symptoms