Age- and speed-dependent modulation of gaits in DSCAM^2Jmutant mice

Abstract

Gaits depend on the interplay between distributed spinal neural networks, termed central pattern generators, generating rhythmic and coordinated movements, primary afferents, and descending supraspinal inputs. Recent studies demonstrated that the mouse displays a rich repertoire of gaits. Changes in gaits occur in mutant mice lacking particular neurons or molecular signaling pathways implicated in the normal establishment of these neural networks. Given the role of the Down syndrome cell adherence molecule (DSCAM) to the formation and maintenance of spinal interneuronal circuits and sensorimotor integration, we have investigated its functional contribution to gaits over a wide range of locomotor speeds using freely walking mice. We show in this study that the DSCAM mutation, while not precluding any gait, impairs the age- and speed-dependent modulation of gaits. It impairs the ability of mice to maintain their locomotion at high treadmill speeds. DSCAM mutation induces the dominance of lateral walk over trot and the emergence of aberrant gaits for mice, such as pace and diagonal walk. Gaits were also more labile in DSCAM mutant mice, i.e., less stable, less attractive, and less predictable than in their wild-type littermates. Our results suggest that the DSCAM mutation affects the behavioral repertoire of gaits in an age- and speed-dependent manner. NEW & NOTEWORTHY Gaits evolve throughout development, up to adulthood, and according to the genetic background. Using mutant mice lacking DSCAM (a cell adherence molecule associated with Down syndrome), we show that the DSCAM mutation alters the repertoire of gaits according to the mouse's age and speed, and prevents fast gaits. Such an incapacity suggests a reorganization of spinal, propriospinal, and supraspinal neuronal circuits underlying locomotor control in DSCAM mutant mice.

Distinct Contributions of Mesencephalic Locomotor Region Nuclei to Locomotor Control in the Freely Behaving Mouse

“…As illustrated by the stick diagram of the hindlimb and EMG recordings ipsilateral to the stimulation site (Figures 6A and 6B1; Movie S2), long photostimulations (long trains of 10-ms pulse duration at 20 Hz for 1 s) of glutamatergic CnF neurons increased motor and postural tone, the angular excursion of the hindlimbs' joints, the height of the iliac crest, as well as the stride height and length. As previously shown [28,29], using the interlimb coupling, the footfall pattern, and the duty cycle of the stance phase, it is possible to identify and characterize locomotor gaits. In addition to changing the intralimb kinematics (bottom panel of Figure 6B1), long photostimulations of glutamatergic CnF neurons also changed inter-limb coordination from a trot (color-coded in blue in Figure 6B1) to a transverse gallop (color-coded in yellow in Figure 6B1).…”

Subtle Roles of Down Syndrome Cell Adhesion Molecules in Embryonic Forebrain Development and Neuronal Migration

“…A spontaneous Dscam null mutation occurring in mice ( Dscam del 17 ) leads to the early post-natal emergence of uncoordinated movements; as adults, these animals additionally display severe hydrocephalus, seizures, aberrant locomotion, and impaired motor learning (Fuerst et al, 2008 ; Xu et al, 2011 ). Similarly, mice carrying a different Dscam null mutant allele ( Dscam 2 J ) present dystonic hypertonia and deficits in locomotor coordination related to abnormalities in central sensorimotor circuitry (Fuerst et al, 2010 ; Lemieux et al, 2016 ; Thiry et al, 2016 , 2018 ; Laflamme et al, 2019 ). Viability of Dscam null mutant mice is highly affected by their genetic background, leading to early post-natal lethality in a C57BL/6 background but survival to adulthood in an inbred C3H background, which suggests that modifier genes partly compensate for early developmental roles of DSCAM (Fuerst et al, 2010 ).…”

Role of DSCAM in the Development of Neural Control of Movement and Locomotion

“…Dscam 2J mutant spinal cords exhibit an abnormal increase in the number of commissural interneurons [92] (Figure 3F,G). Several signaling pathways contribute to normal development of the spinal circuit, and especially left-right coordination.…”

“…Adult Dscam 2J mutant mice exhibit a reduced repertoire of gaits with a reduced maximal locomotor speed [92]. In addition to impairing the ability of mice to maintain high treadmill speed with running gaits, the Dscam mutation also induces the dominance of lateral walk over trot and the emergence of aberrant gaits, such as diagonal walk and pace, rarely reported in the mouse (Figure 2D).…”

“…Using these isolated spinal cord preparations [30], it has been shown that Dscam 2J mutant spinal cords exhibit changes in locomotor pattern and rhythm, with an increased variability in their step-cycle duration (i.e., locomotor frequency) and in the duration of their flexor-and extensor-related activities. Furthermore, whereas the flexor-extensor alternation is normal, Dscam 2J mutant spinal cord preparations show a decrease in their left-right alternation, with episodes of synchronization, which persists though adulthood [72,92] (Figure 3E).…”