White Matter Alterations in <b><i>Fmr1</i></b> Knockout Mice during Early Postnatal Brain Development

Abstract

Fragile X syndrome (FXS) is the most commonly inherited form of intellectual disability ascribed to the autism spectrum disorder. Studies with FXS patients have reported altered white matter volume compared to controls. The Fmr1 knockout (KO) mouse, a model for FXS, showed evidence of delayed myelination during postnatal brain development. In this study, we examined several white matter regions in the male Fmr1 KO mouse brain compared to male wild-type (WT) mice at postnatal days (PND) 18, 21, 30, and 60, which coincide with critical stages of myelination and postnatal brain development. White matter volume, T₂ relaxation time, and magnetization transfer ratio (MTR) were measured using magnetic resonance imaging and myelin content was determined with histological staining of myelin. Differences in the developmental accumulation of white matter and myelin between Fmr1 KO and WT mice were observed in the corpus callosum, external and internal capsules, cerebral peduncle, and fimbria. Alterations were more predominant in the external and internal capsules and fimbria of Fmr1 KO mice, where the MTR was lower at PND 18, then elevated at PND 30, and again lower at PND 60 compared to the corresponding regions in WT mice. The pattern of changes in MTR were similar to those observed in myelin staining and could be related to the altered protein synthesis that is a hallmark of FXS. While no significant changes in white matter volumes and T₂ relaxation time between the Fmr1 KO and WT mice were observed, the altered pattern of myelin staining and MTR, particularly in the external capsule, reflecting the abnormalities associated with myelin content is suggestive of a developmental delay in the white matter of Fmr1 KO mouse brain. These early differences in white matter during critical developmental stages may contribute to altered brain networks in the Fmr1 KO mice.

Structural and Lipidomic Alterations of Striatal Myelin in 16p11.2 Deletion Mouse Model of Autism Spectrum Disorder

“…FPKM, Fragments per kilobase of transcript per million mapped reads. regions at P60 (Shi et al, 2019). In addition, in chromodomainhelicase-DNA-binding protein 8 (Chd8) conditional knockout mice where Chd8 is specifically ablated in oligodendrocyte lineage cells, autism-like behavioral changes appeared to correlate with myelin microstructural changes in the striatum (Kawamura et al, 2020).…”

Consumption of Breast Milk Is Associated with Decreased Prevalence of Autism in Fragile X Syndrome

“…Thus, it has been hypothesized that an inadequate supply of IGF-1 results in abnormal myelination of brain neurons leading to the development of autism [ 28 , 29 ]. Delayed myelination is observed in Fmr1 KO mice [ 30 , 31 ], and genetic reduction of insulin-like growth factor receptor-1 (IGF-1R) or treatment with a synthetic analog of a naturally occurring neurotropic peptide derived from IGF-1 corrects a multitude of disease phenotypes in Fmr1 KO mice [ 32 , 33 ]. Breast milk has a higher quantity of human IGF-1 than bovine milk or infant formula [ 34 ] and is associated with elevated IGF-1 in preterm infants [ 35 ] and altered white matter volume in boys [ 36 ].…”

Role of PARP1 in oligodendrocyte differentiation during developmental myelination and remyelination after myelin damage

“…The identification of these proteins provided positive controls for our unbiased approaches. Very interestingly, we identified some novel PARylated proteins with reported functions in oligodendroglial development, such as the RNA/DNA-binding protein Fus (Guzman et al, 2020) and Mecp2 (Nguyen et al, 2013) and the RNA-binding protein Qki (Thangaraj et al, 2017;Zhou et al, 2020) and Fmr1 (Giampetruzzi et al, 2013;Shi et al, 2019) (Fig. 6D).…”