Mice born preterm develop gait dystonia and reduced cortical parvalbumin immunoreactivity

Abstract

Preterm birth leading to cerebral palsy (CP) is the most common cause of childhood dystonia, a movement disorder that is debilitating and often treatment refractory. Dystonia has been typically associated with dysfunction of striatal cholinergic interneurons, but clinical imaging data suggests that cortical injury may best predict dystonia following preterm birth. Furthermore, abnormal sensorimotor cortex inhibition has been found in many studies of non-CP dystonias. To assess the potential for a cortical etiology of dystonia following preterm birth, we developed a new model of preterm birth in mice. Noting that term delivery in mice on a C57BL/6J background is embryonic day 19.1 (E19.1), we induced preterm birth at the limits of pup viability at embryonic day (E) 18.3, equivalent to human 22 weeks gestation. Mice born preterm demonstrate display clinically validated metrics of dystonia during gait (leg adduction amplitude and variability) and also demonstrate reduced parvalbumin immunoreactivity in the sensorimotor cortex, suggesting dysfunction of cortical parvalbumin-positive inhibitory interneurons. Notably, reduced parvalbumin immunoreactivity or changes in parvalbumin-positive neuronal number were not observed in the striatum. These data support the association between cortical dysfunction and dystonia following preterm birth. We propose that our mouse model of preterm birth can be used to study this association and potentially also study other sequelae of extreme prematurity.

Keywords: Prematurity; cerebral palsy; dystonia; parvalbumin-positive interneurons.

Figure 1.

Treadmill design.

Figure 2.

Gestational ages (A) and litter sizes (B) of mice born preterm (n=6 litters) and term-born controls (n=5 litters). *T-test

Figure 3.

Locomotor impairment during treadmill gait (A, two-way repeated measures ANOVA) and Open field (B, T-test). Mice born preterm demonstrate a reduced proportion of time in bipedal support during gait.

Figure 4.

Clinically validated dystonic gait features during treadmill (A, two-way repeated measures ANOVA) and open field (B, T-test). During treadmill gait, mice demonstrate decreased foot angle minimum and variance (A), but during open field, this is only apparent during the less stable bipedal support period of gait.

Figure 5.

Example parvalbumin immunohistochemistry in mice born at term (A, C, E) and preterm (B, D, E) in an axial brain slice taken at 0.7 mm anterior to bregma (A, B). Regions magnified in C-F are indicated in A and B with rectangular boxes. C,D – sensorimotor cortex. E, F – striatum. Note that there is reduced parvalbumin immunoreactivity in this mouse born preterm compared to a term born control in the sensorimotor cortex (D vs. C) but not in the striatum (F vs. E).

Figure 6.

Parvalbumin immunoreactivity in the sensorimotor cortex (A) and striatum (B). Mice born preterm demonstrate reduced parvalbumin immunoreactivity compared to term born controls in the sensorimotor cortex (A), but not in the striatum (B). *T-test