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.
Highlights
It is well admitted that perinatal brain damage and neurodevelopmental disorders (NDD) are usually related to several conditions, such as neonatal encephalopathy, perinatal arterial ischemic stroke, systemic infections, and premature birth [1]
This study is the first to show the early and enduring functional disorganization of neuromuscular interactions after mild intrauterine hypoperfusion (MIUH) in a rat model that recapitulates the diversity of the symptoms observed in children with encephalopathy of prematurity [6]
MIUH in rats led to [1] reduced post-activation depression (PAD) at P4–P6, indicative of early hyperreflexia and spasticity, [2] an early reduction of the oligomeric and monomeric forms of KCC2, which regulates chloride homeostasis and cell excitability, [3] reduced PAD in adult rats, suggestive of enduring hyperreflexia and spasticity in adulthood, [4] changes in muscle contractile properties and phenotype in young-adults, and [5] cortical hyperexcitability in the adult sensorimotor cortex devoted to the hind limb representation
Summary
It is well admitted that perinatal brain damage and neurodevelopmental disorders (NDD) are usually related to several conditions, such as neonatal encephalopathy, perinatal arterial ischemic stroke, systemic infections, and premature birth [1]. About 40% of extremely born preterm children (24–32 weeks of gestation) develop moderate to severe sensorimotor and/or cognitive impairments, while the rest of these very preterm children often exhibit minor motor, behavioral, and cognitive disorders. Encephalopathy of prematurity (EP) is mainly characterized by gray matter dysmaturation and reduction, diffuse white matter injury (WMI) related to abnormal oligodendroglial precursor maturation leading to hypomyelination, minor to mild sensorimotor, behavioral and cognitive disorders, and often results in CP [1]. The relations between the NDDs, brain damage, perinatal hypoxiaischemia, and neuroinflammation are not completely clear and understood [3, 5], we recently developed a rodent model of EP, based on prenatal ischemia [6] which better corresponds to mild intrauterine hypoperfusion (MIUH) [7]
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