Impaired myelination of the human hippocampal formation in Down syndrome

Abstract

Myelination is considered as one of the last steps of neuronal development and is essential to the physiologically matured function of afferent and efferent pathways. In the present study, myelin formation was examined in the human fetal, postnatal and adult hippocampal formation in Down syndrome and in age-matched controls with immunohistochemistry detecting a protein component of the myelin sheath, the myelin basic protein synthesized by oligodendroglial cells. Myelination is mainly a postnatal event in the hippocampal formation of both healthy controls and in patients with Down syndrome. In patients with Down syndrome the sequence of myelination of the hippocampal formation followed a similar developmental pattern to that in controls. However, myelin formation was generally delayed in Down syndrome compared to age-matched controls. In addition, in the hilus of the dentate gyrus a decreased density of myelinated axons was detected from the start of myelination until adulthood. The majority of local axons (mossy fibers) are not myelinated in the hilar region and myelinated fibers arriving in the hilus come mainly from the subcortical septal nuclei. Since intact septo-hippocampal connections are necessary for memory formation, we hypothesize that decreased myelination in the hilus may contribute to the mental retardation of Down syndrome patients.

Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination

“…Recent evidence in animal models indicates that ongoing myelin remodeling throughout life may be important for learning, behavior, and cognition throughout adulthood (Liu et al, 2012; McKenzie et al, 2014). This is in agreement both with previous studies showing that DS children manifest learning and memory problems in late infancy which often worsen in adolescence (Koo et al, 1992; Lanfranchi et al, 2010) and with post-mortem studies that show reduced myelin content (Abraham et al, 2012; Wisniewski, 1990; Wisniewski and Schmidt-Sidor, 1989) and fewer oligodendrocytes in DS striatum (Karlsen and Pakkenberg, 2011). …”

Evidence of altered age-related brain cytoarchitecture in mouse models of down syndrome: a diffusional kurtosis imaging study

“…In humans, a myelination delay has been reported affecting tracks with late and slow cycle of myelination, such as associated and intercortical fibers of the frontal-temporal connections (66). Also, previous reports in humans (64) showed that the sequence of myelination in hippocampus formation of both DS and controls are similar, but the number of myelinated fibers and their density are lower in DS when compared to age-matched controls. Interestingly, this difference between the density of myelinated fibers of DS patients and controls is mild in the first few months after birth, but increases and becomes more evident at older ages.…”

“…The increased kurtosis values in the frontal cortex of 2-month old TS mice could conceivably reflect increased diffusional heterogeneity due to the abnormal cortical lamination, less coherence in neurite orientations and smaller, less branched and less spinous dendrites as previously described in this region (20,63)”. The lower DK values in the dorsal hippocampus of TS mice at this age may be related to both the defects in axonal spread and enlargements of dendritic spines, causing diffusion dead-space microdomains (21–24), as well as abnormal myelination of the hippocampus formation, as has been described in humans (64). At 5 months of age, TS mice showed lower K ⊥ values in the striatum (ST; Table 2), which may also be related to abnormality in the myelination process.…”

Cognitive Impairment, Neuroimaging, and Alzheimer Neuropathology in Mouse Models of Down Syndrome

“…Previous studies suggest that increased kurtosis values in the frontal cortex of 2-month old Ts65Dn mice reflect increased heterogeneity due to abnormal cortical lamination and altered structural dendrite and spine abnormalities in this region [98, 99]. Also, lower DK values in the dorsal hippocampus of Ts65Dn mice may be related to defects in axonal spread and enlargements of dendritic spines [98, 99] causing diffusion dead-space micro-domains, as well as, abnormal myelination of the hippocampal formation, as described in humans [100, 101]. Lower radial kurtosis (K ⏊ ) values in the striatum may also be related to abnormalities in the myelination process [101].…”