Early Functional Impairment of Sensory-Motor Connectivity in a Mouse Model of Spinal Muscular Atrophy

• Published in: Neuron (Cambridge, Mass.) Vol. 69; no. 3; pp. 453 - 467
• Main Authors: Mentis, George Z., Blivis, Dvir, Liu, Wenfang, Drobac, Estelle, Crowder, Melissa E., Kong, Lingling, Alvarez, Francisco J., Sumner, Charlotte J., O'Donovan, Michael J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10-02-2011; Elsevier Limited
• Subjects: Age Factors; Amyotrophic lateral sclerosis; Animals; Animals, Newborn; Disease Models, Animal; Mice; Mice, Transgenic; Motor Neurons - pathology; Motor Neurons - physiology; Muscular Atrophy, Spinal - genetics; Muscular Atrophy, Spinal - pathology; Muscular Atrophy, Spinal - physiopathology; Muscular system; Rodents; Sensory Receptor Cells - pathology; Sensory Receptor Cells - physiology; Spinal cord; Studies; Synapses - pathology; Synapses - physiology
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2010.12.032

To define alterations of neuronal connectivity that occur during motor neuron degeneration, we characterized the function and structure of spinal circuitry in spinal muscular atrophy (SMA) model mice. SMA motor neurons show reduced proprioceptive reflexes that correlate with decreased number and function of synapses on motor neuron somata and proximal dendrites. These abnormalities occur at an early stage of disease in motor neurons innervating proximal hindlimb muscles and medial motor neurons innervating axial muscles, but only at end-stage disease in motor neurons innervating distal hindlimb muscles. Motor neuron loss follows afferent synapse loss with the same temporal and topographical pattern. Trichostatin A, which improves motor behavior and survival of SMA mice, partially restores spinal reflexes, illustrating the reversibility of these synaptic defects. Deafferentation of motor neurons is an early event in SMA and may be a primary cause of motor dysfunction that is amenable to therapeutic intervention.
► Reduced proprioceptive reflex function precedes loss of motor neurons in SMA mice ► Motor neurons in SMA mice lose VGluT1 primary afferent terminals ► Medial motor neurons are affected earlier than lateral motor neurons ► Treatment with TSA improves reflex function and reverses motor neuron cell death