Large-Scale Phenotyping of an Accurate Genetic Mouse Model of JNCL Identifies Novel Early Pathology Outside the Central Nervous System

Abstract

Cln3Δex7/8 mice harbor the most common genetic defect causing juvenile neuronal ceroid lipofuscinosis (JNCL), an autosomal recessive disease involving seizures, visual, motor and cognitive decline, and premature death. Here, to more thoroughly investigate the manifestations of the common JNCL mutation, we performed a broad phenotyping study of Cln3Δex7/8 mice. Homozygous Cln3Δex7/8 mice, congenic on a C57BL/6N background, displayed subtle deficits in sensory and motor tasks at 10–14 weeks of age. Homozygous Cln3Δex7/8 mice also displayed electroretinographic changes reflecting cone function deficits past 5 months of age and a progressive decline of retinal post-receptoral function. Metabolic analysis revealed increases in rectal body temperature and minimum oxygen consumption in 12–13 week old homozygous Cln3Δex7/8mice, which were also seen to a lesser extent in heterozygous Cln3Δex7/8 mice. Heart weight was slightly increased at 20 weeks of age, but no significant differences were observed in cardiac function in young adults. In a comprehensive blood analysis at 15–16 weeks of age, serum ferritin concentrations, mean corpuscular volume of red blood cells (MCV), and reticulocyte counts were reproducibly increased in homozygous Cln3 Δ ex7/8 mice, and male homozygotes had a relative T-cell deficiency, suggesting alterations in hematopoiesis. Finally, consistent with findings in JNCL patients, vacuolated peripheral blood lymphocytes were observed in homozygous Cln3 Δ ex7/8 neonates, and to a greater extent in older animals. Early onset, severe vacuolation in clear cells of the epididymis of male homozygous Cln3 Δ ex7/8 mice was also observed. These data highlight additional organ systems in which to study CLN3 function, and early phenotypes have been established in homozygous Cln3 Δ ex7/8 mice that merit further study for JNCL biomarker development.

Efficacy of phosphodiesterase‐4 inhibitors in juvenile Batten disease (CLN3)

“…Because inflammation has been linked to pathology in JNCL, it is likely that PDE4 inhibitors may dampen inflammation, which would be desirable in the CNS to limit deleterious inflammation in response to dying neurons and autoantibody formation that is characteristic of the disease 58, 59. We did not examine potential systemic effects of PDE4 inhibitors in the current report, because there are no peripheral biomarkers that have been identified in JNCL and the few systemic changes reported to be altered in Cln3 Δex7/8 mice are modest in nature 60. However, we did not observe any adverse effects on blood chemistry values throughout the 6‐month duration of PDE4 inhibitor treatment in either Cln3 Δex7/8 or WT animals.…”

Behavioral and monoamine perturbations in adult male mice with chronic inflammation induced by repeated peripheral lipopolysaccharide administration

“…After a 5-min resting period (following the open field test), mice were placed upright on the top of a gauze-wrapped vertical metal pole (1 cm in diameter and 55 cm in height). The maximum turning time allowed was 60 s and the total time (complete turn + descent) per trial was 120 s [52]. If a mouse did not turn within the first 60 s, it was gently guided and a maximum measurement (60 s) was recorded.…”

An ENU Mutagenesis-Derived Mouse Model with a Dominant Jak1 Mutation Resembling Phenotypes of Systemic Autoimmune Disease

“…A macroscopic examination was performed in combination with histological analysis of all organs using H&E stain, as described previously. 24 The analysis was complemented by histochemical studies for Masson's trichrome, Gomori's method for reticulin, 25 and periodic acid Schiffs stain. Images for histomorphometry were taken by the slide-scanning system, NanoZoomer 2.0 HT (Hamamatsu Photonics K.K.…”