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Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy.

Nature neuroscience | Aug 29, 2017

Behavioral deficits in neurodegenerative diseases are often attributed to the selective dysfunction of vulnerable neurons via cell-autonomous mechanisms. Although vulnerable neurons are embedded in neuronal circuits, the contributions of their synaptic partners to disease process are largely unknown. Here we show that, in a mouse model of spinal muscular atrophy (SMA), a reduction in proprioceptive synaptic drive leads to motor neuron dysfunction and motor behavior impairments. In SMA mice or after the blockade of proprioceptive synaptic transmission, we observed a decrease in the motor neuron firing that could be explained by the reduction in the expression of the potassium channel Kv2.1 at the surface of motor neurons. Chronically increasing neuronal activity pharmacologically in vivo led to a normalization of Kv2.1 expression and an improvement in motor function. Our results demonstrate a key role of excitatory synaptic drive in shaping the function of motor neurons during development and the contribution of its disruption to a neurodegenerative disease.

Pubmed ID: 28504671 RIS Download

Mesh terms: Action Potentials | Animals | Cell Survival | Disease Models, Animal | Kainic Acid | Metalloendopeptidases | Mice | Mice, Transgenic | Motor Neurons | Muscular Atrophy, Spinal | Neuromuscular Junction | Proprioception | Reflex, Righting | Shab Potassium Channels | Survival of Motor Neuron 1 Protein | Survival of Motor Neuron 2 Protein | Synapses | Tetanus Toxin

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