Maternal behavior impacts during development of the PITX3 Parkinson’s mouse

Abstract

The Pitx3ak/2J aphakia mouse model exhibits useful characteristics for the study of Parkinson’s disease. Research has revealed a 90% reduction in substantia nigra pars compacta (SNc) dopaminergic neurons in adult Pitx3 mice, exceeding the 80% loss threshold for symptoms seen in humans with Parkinson’s disease. Similarly, these mice display motor deficits that are reversed by L-DOPA. Our work has shown these behavioral deficits emerge prior to birth, raising the possibility of altered maternal-pup interaction. In the current study, we hypothesized that behavioral outcomes in adult mice are altered depending on the genetic composition of the litter during early rearing. This hypothesis is being tested by mating Pitx3 heterozygous females to homozygous (mutant) males in order to produce both heterozygous (control) and mutant offspring in roughly equal numbers. On the day after birth (Postnatal day 1, P1), mouse pups were fostered into three different litter types: (a) mixed litter with equal numbers of mutant and control pups, (b) all mutant offspring, and (c) all control pups. Males and females from each litter and condition were tested with measures sensitive to nigrostriatal impairment at P60. These behavioral tests are: (a) open field test, (b) pole climb, and (c) swim test. In order to determine if any differences in maternal behavior are due to chemical signals from the pups themselves as opposed to behavioral differences, urine will be collected from pups on each of the testing days, and analyzed by NMR Spectroscopy for metabolomic profiles. We expect to find results that suggest behavioral functioning is impacted by early rearing environment and is independent of genotype. Consequently, design and husbandry considerations may be important epigenetic factors to consider in studies with genetically altered mice.