116. Inflammation and Impaired Neural Differentiation in CCDC39-Deficient Rat Model of Neonatal Hydrocephalus
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Authors: Eri Iwasawa; Andrew Emmert; Crystal Shula, BS; Preston Schultz; Yueh-Chiang Hu, PhD; Francesco Mangano, DO; June Goto, PhD (Cincinnati, OH)
Neonatal hydrocephalus is a major congenital brain anomaly which often requires cerebral spinal fluid (CSF) diversion. Although it frequently accompanies cognitive deficits, pathogenesis underlying the impaired neural differentiation is widely unknown.
Using CRISPR/Cas9 genome editing system, we induced a gene mutation within the coiled-coil domain containing protein 39 (Ccdc39) gene in rats, which develops neonatal hydrocephalus due to the CSF flow retardation caused by ependymal cilia dysfunction in the forebrain ventricles. Some Ccdc39 heterozygous male rats were crossed with the L1cam mutation carrier female to create L1cam/Ccdc39 double mutant rats. Brains from Ccdc39 mutant, double mutant, and control rats aged postnatal day P1 through P30 were analysed with immunohistochemistry. Three Ccdc39 mutant rats underwent stereotactic guided insertion of ventriculo-subcutaneous shunt (VSS) at P7-8, and brains histology at P11 was compared with the age-matched hydrocephalic Ccdc39 mutants without VSS. Intracranial pressures (ICP) were measured at P7 in Ccdc39 mutant and control rats with telemetry technology.
Ventriculomegaly started at P5 in Ccdc39 mutants with the upregulation of pro-inflammatory cytokine, monocyte chemoattractant protein-1, and macrophage invasion to the periventricular white matter. Inflammatory cell invasion was exacerbated with development of hydrocephalus. In the L1cam/Ccdc39 double mutant, ventriculomegaly started at P1 with macrophages seen in the subventricular zone. Myelination and neurofilament density were significantly impaired at P11 in Ccdc39 mutants, which was improved but not completely reversed by VSS. ICP was significantly elevated in Ccdc39 mutants compared to controls (5.8 versus 3.8 mmHg).
Ccdc39 neonatal hydrocephalus rat imitates the immature neural differentiation in human neonatal hydrocephalus, and inflammatory reactions may play a role in pathogenesis, which possibly accelerated the hydrocephalus development in double mutants. Optimization of shunt surgery using ICP measurement, along with anti-inflammatory drug may lead to a better outcome.