Abstract
The broad spectrum of disabilities caused by white matter injury (WMI) cannot be explained simply by hypomyelination. Synaptic injury in the thalamus may be related to disabilities in WMI survivors. Neuronal injury in the thalamus has been found most commonly in autopsy cases of preterm WMI. We hypothesized that hypoxia/ischemia (HI) in neonatal rats results in synaptic abnormalities in the thalamus that contribute to disabilities in WMI survivors. We examined changes in synapses in a neonatal rat model of HI-induced WMI. Right common carotid artery ligation and hypoxia (8% oxygen for 2.5 hours (h)) were performed in three-day-old Sprague-Dawley rats. We found HI rats performed worse in the Morris water maze test than sham rats, suggesting long-term cognition impairment after HI injury. A loss of synapses in the thalamus accompanied by hypomyelination and oligodendrocytes (OLs) reduction was observed. At the ultrastructural level, reductions in active zone (AZ) length and postsynaptic density (PSD) thickness were detected at 2 weeks after HI exposure. Furthermore, increased expression of synaptophysin and PSD-95 in both groups was observed from 3 days (d) to 21 d after hypoxic/ischemic (HI) injury. PSD-95 expression was significantly lower in HI rats than in sham rats from 14 d to 21 d after HI injury, and synaptophysin expression was significantly lower in HI rats from 7 d to 14 d after HI injury. However, no significant difference in synaptophysin expression was observed between HI rats and sham rats at 21 d after HI injury. The results demonstrated synaptic abnormalities in the thalamus accompanied by hypomyelination in WMI in response to HI exposure, which may contribute to the diverse neurological defects observed in WMI patients. Although synaptic reorganization occurred as a compensatory response to HI injury, the impairments in synaptic transmission were not reversed.
Highlights
Cerebral white matter injury (WMI) is the leading contributor to neurodevelopmental disabilities in premature infants
Premyelinating oligodendrocytes, which have been reported to be highly susceptible to HI and inflammation, have been shown to be the main cell target in WMI [3, 5, 9, 10]. e broad spectrum of disabilities caused by WMI, including behavioral deficits, appears to be related to not myelination failure. e neuroanatomic substrate of diverse disabilities of WMI survivors remains unclear. e thalamus is related to cognition via extensive connections
All animal experiments were approved by the Animal Ethical Committee of China Medical University, Shenyang, China (2017PS140K). e animal model for WMI was induced according to the method provided by Vannucci et al [20]. e surgery was performed following inhalation anesthesia. e right common carotid artery of 3-day-old (P3) Sprague-Dawley rats was double-ligated after inhalation of anesthesia, and a cut was made between the ligatures as described previously [21]
Summary
Synaptic injury in the thalamus may be related to disabilities in WMI survivors. We hypothesized that hypoxia/ischemia (HI) in neonatal rats results in synaptic abnormalities in the thalamus that contribute to disabilities in WMI survivors. We examined changes in synapses in a neonatal rat model of HI-induced WMI. A loss of synapses in the thalamus accompanied by hypomyelination and oligodendrocytes (OLs) reduction was observed. Increased expression of synaptophysin and PSD-95 in both groups was observed from 3 days (d) to 21 d after hypoxic/ischemic (HI) injury. No significant difference in synaptophysin expression was observed between HI rats and sham rats at 21 d after HI injury. E results demonstrated synaptic abnormalities in the thalamus accompanied by hypomyelination in WMI in response to HI exposure, which may contribute to the diverse neurological defects observed in WMI patients.
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