Mild Intrauterine Hypoperfusion Leads to Lumbar and Cortical Hyperexcitability, Spasticity, and Muscle Dysfunctions in Rats: Implications for Prematurity

Abstract

Intrauterine ischemia-hypoxia is detrimental to the developing brain and leads to white matter injury (WMI), encephalopathy of prematurity (EP), and often to cerebral palsy (CP), but the related pathophysiological mechanisms remain unclear. In prior studies, we used mild intrauterine hypoperfusion (MIUH) in rats to successfully reproduce the diversity of clinical signs of EP, and some CP symptoms. Briefly, MIUH led to inflammatory processes, diffuse gray and WMI, minor locomotor deficits, musculoskeletal pathologies, neuroanatomical and functional disorganization of the primary somatosensory and motor cortices, delayed sensorimotor reflexes, spontaneous hyperactivity, deficits in sensory information processing, memory and learning impairments. In the present study, we investigated the early and long-lasting mechanisms of pathophysiology that may be responsible for the various symptoms induced by MIUH. We found early hyperreflexia, spasticity and reduced expression of KCC2 (a chloride cotransporter that regulates chloride homeostasis and cell excitability). Adult MIUH rats exhibited changes in muscle contractile properties and phenotype, enduring hyperreflexia and spasticity, as well as hyperexcitability in the sensorimotor cortex. Taken together, these results show that reduced expression of KCC2, lumbar hyperreflexia, spasticity, altered properties of the soleus muscle, as well as cortical hyperexcitability may likely interplay into a self-perpetuating cycle, leading to the emergence, and persistence of neurodevelopmental disorders (NDD) in EP and CP, such as sensorimotor impairments, and probably hyperactivity, attention, and learning disorders.

Spinal Hyper-Excitability and Altered Muscle Structure Contribute to Muscle Hypertonia in Newborns After Antenatal Hypoxia-Ischemia in a Rabbit Cerebral Palsy Model

“…A recent study on a rat model of fetal hypoperfusion (68) demonstrated persistent increase of motoneuron excitability based on decreased RDD of H-reflex, similar to data in our rabbit data. Neuronal hyper- reflexivity has been attributed to decreased expression of KCC2 in spinal cord of P8 rats after prenatal hypoperfusion.…”

Impact of intrauterine hypoxia on adolescent and adult cognitive function in rat offspring: sexual differences and the effects of spermidine intervention

“…Longa scoring is based on neurological behavioral performance; therefore, the peripheral nervous system function of the animal might directly affect the result. A previous study reported that the muscle contractile properties of rat offspring with prenatal ischemia induced by unilateral ligation of the uterine artery were not changed in the P28 group but were significantly decreased in adult offspring [37]. Therefore, the different effects of IUH on the neurological function of offspring at different ages might be due to the late maturation of muscle.…”

Loss of non‐canonical KCC 2 functions promotes developmental apoptosis of cortical projection neurons

“…Downregulation of KCC2 has been reported in human preterm infants with white matter damage [66], suggesting that an early loss of KCC2 may be related to cerebral palsy and encephalopathy of prematurity [67]. Perturbations in neurodevelopmental apoptosis are thought to contribute to early-onset epileptic encephalopathies [68,69].…”