title: Preservation of VGLUT1 synapses on ventral calbindin-immunoreactive interneurons and normal locomotor function in a mouse model of spinal muscular atrophy.
abstract: Dysfunction in sensorimotor synapses is one of the earliest pathological changes observed in a mouse model [spinal muscular atrophy (SMA)Δ7] of spinal muscular atrophy. Here, we examined the density of proprioceptive and cholinergic synapses on calbindin-immunoreactive interneurons ventral to the lateral motor column. This population includes inhibitory Renshaw interneurons that are known to receive synaptic input from muscle spindle afferents and from motoneurons. At postnatal day (P)13, near the end stage of the disease, the somatic area of calbindin(+) neurons in the L1/L2 and L5/L6 segments was reduced in SMAΔ7 mice compared with controls. In addition, the number and density of terminals expressing the glutamate vesicular transporter (VGLUT1) and the vesicular acetylcholine transporter (VAChT) were increased on calbindin(+) cells in the L1-L2 but not in the L5-L6 segments of SMAΔ7 mice. In addition, the isolated spinal cord of SMA mice was able to generate locomotor-like activity at P4-P6 in the presence of a drug cocktail or in response to dorsal root stimulation. These results argue against a generalized loss of proprioceptive input to spinal circuits in SMA and suggest that the loss of proprioceptive synapses on motoneurons may be secondary to motoneuron pathology. The increased number of VGLUT1(+) and VAChT(+) synapses on calbindin(+) neurons in the L1/L2 segments may be the result of homeostatic mechanisms. Finally, we have shown that abnormal locomotor network function is unlikely to account for the motor deficits observed in SMA mice at P4-6.
authors.affiliation: Section on Developmental Neurobiology, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
authors.forename: Vatsala
authors.initials: V
authors.lastname: Thirumalai
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Behrend
authors.forename: Swetha
authors.initials: S
authors.lastname: Birineni
authors.forename: Wenfang
authors.initials: W
authors.lastname: Liu
authors.forename: Dvir
authors.initials: D
authors.lastname: Blivis
authors.forename: Michael J
authors.initials: MJ
authors.lastname: O'Donovan
mesh_terms: D000818:Animals; D064026:Calbindins; D059329:Cholinergic Neurons / Q000737:chemistry / Q000502:physiology*; D004195:Disease Models, Animal; D007395:Interneurons / Q000737:chemistry / Q000502:physiology*; D008124:Locomotion; D051379:Mice; D008817:Mice, Mutant Strains; D009046:Motor Neurons / Q000502:physiology; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000503:physiopathology; D064030:S100 Calcium Binding Protein G / Q000032:analysis; D013116:Spinal Cord / Q000166:cytology / Q000503:physiopathology*; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics; D013569:Synapses / Q000737:chemistry / Q000502:physiology*; D050494:Vesicular Acetylcholine Transport Proteins / Q000032:analysis; D050598:Vesicular Glutamate Transport Protein 1 / Q000032:analysis*
chemical_list: D064026:Calbindins; D064030:S100 Calcium Binding Protein G; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D050494:Vesicular Acetylcholine Transport Proteins; D050598:Vesicular Glutamate Transport Protein 1