Reduced subventricular zone proliferation and white matter damage in juvenile ferrets with kaolin-induced hydrocephalus

Abstract

Hydrocephalus is a neurological condition characterized by altered cerebrospinal fluid (CSF) flow with enlargement of ventricular cavities in the brain. A reliable model of hydrocephalus in gyrencephalic mammals is necessary to test preclinical hypotheses. Our objective was to characterize the behavioral, structural, and histological changes in juvenile ferrets following induction of hydrocephalus. Fourteen-day old ferrets were given an injection of kaolin (aluminum silicate) into the cisterna magna. Two days later and repeated weekly until 56 days of age, magnetic resonance (MR) imaging was used to assess ventricle size. Behavior was examined thrice weekly. Compared to age-matched saline-injected controls, severely hydrocephalic ferrets weighed significantly less, their postures were impaired, and they were hyperactive prior to extreme debilitation. They developed significant ventriculomegaly and displayed white matter destruction. Reactive astroglia and microglia detected by glial fibrillary acidic protein (GFAP) and Iba-1 immunostaining were apparent in white matter, cortex, and hippocampus. There was a hydrocephalus-related increase in activated caspase 3 labeling of apoptotic cells (7.0 vs. 15.5%) and a reduction in Ki67 labeling of proliferating cells (23.3 vs. 5.9%) in the subventricular zone (SVZ). Reduced Olig2 immunolabeling suggests a depletion of glial precursors. GFAP content was elevated. Myelin basic protein (MBP) quantitation and myelin biochemical enzyme activity showed early maturational increases. Where white matter was not destroyed, the remaining axons developed myelin similar to the controls. In conclusion, the hydrocephalus-induced periventricular disturbances may involve developmental impairments in cell proliferation and glial precursor cell populations. The ferret should prove useful for testing hypotheses about white matter damage and protection in the immature hydrocephalic brain.

Keywords: 2′3′cyclic nucleotide 3′phosphodiesterase; APP; Behavior; CGalT; CNPase; COX; CSF; DAB; DG; ELISA; Ferret; GFAP; GLM; GPC-PP; H&E; Hydrocephalus; ISVZ; MBP; MR; Magnetic resonance (MR) imaging; NADH; NF; NRC; National Research Council; OSVZ; P; PBS; SDH; SEM; SVZ; TE; TR; VZ; White matter; amyloid precursor protein; ceramide galactosyltransferase; cerebrospinal fluid; cytochrome c oxidase; dentate gyrus; diaminobenzidine; echo time; enzyme linked immunosorbent assay; general linear model; glial fibrillary acidic protein; glycerylphosphorylcholine phosphocholine phosphodiesterase; hematoxylin and eosin; inner subventricular zone; magnetic resonance; myelin basic protein; neurofilament; nicotinamide adenine dinucleotide; outer subventricular zone; p-nitrophenylphosphorylcholine; pNPP; phosphate-buffered saline; postnatal day; recovery time; standard error of the mean; subventricular zone; succinic dehydrogenase; ventricular zone.