Quantitative analysis of locomotor defects in neonatal mice lacking proprioceptive feedback

Abstract

Proprioceptive feedback derived from specialized receptors in skeletal muscle is critical in forming an accurate map of limb position in space, and is used by the central nervous system to plan future movements and to determine accuracy of executed movements. Knockout mouse strains for genes expressed by proprioceptive sensory neurons have been generated that result in generalized motor deficits, but these deficits have not been quantitatively characterized. Here we characterize a conditional knockout mouse model wherein proprioceptive sensory neuron synaptic transmission has been blocked by selective ablation of munc18-1, a synaptic vesicle associated protein required for fusion of synaptic vesicles with the plasma membrane. Proprioceptive munc18-1 conditional mutants are impaired in surface righting – a dynamic postural adjustment task – and display several specific deficits in pivoting, an early locomotor behavior. Before the emergence of forward locomotion during postnatal development, animals explore their surroundings through pivoting, or rotating the upper torso around the relatively immobile base of the hind limbs. 3-D kinematic analysis was used to quantitatively describe this pivoting behavior at postnatal days 5 and 8 in control and munc18-1 conditional mutants. Mutant animals also pivot, but demonstrate alterations in movement strategy and in postural placement of the forelimbs during pivoting when compared to controls. In addition, brief forelimb stepping movements associated with pivoting are altered in mutant animals. Step duration and step height are increased in mutant animals. These results underscore the importance of proprioceptive feedback even at early stages in postnatal development.