Maternal autoimmune antibodies alter the dendritic arbor and spine numbers in the infragranular layers of the cortex.

An association between maternal IgG antibodies reactive against proteins in fetal brain and an outcome of autism in the child has been identified. Using a mouse model of prenatal intraventricular administration of autism-specific maternal IgG, we demonstrated that these antibodies produce behavioral alterations similar to those in children with ASD. We previously demonstrated that these antibodies bind to radial glial stem cells (RG) and observed an increase in the number of divisions of translocating RG in the developing cortex. We also showed an alteration in brain size and as well as a generalized increased of neuronal volume in adult mice. Here, we used our intraventricular mouse model of antibody administration, followed by Golgi and Neurolucida analysis to demonstrate that during midstages of neurogenesis these maternal autism-specific antibodies produced a consistent decrease in the number of spines in the infragranular layers in the adult cortical areas analyzed. Specifically, in the frontal cortex basal dendrites of layer V neurons were decreased in length and volume, and both the total number of spines-mature and immature-and the spine density were lower than in the control neurons from the same region. Further, in the occipital cortex layer VI neurons presented with a decrease in the total number of spines and in the spine density in the apical dendrite, as well as decrease in the number of mature spines in the apical and basal dendrites. Interestingly, the time of exposure to these antibodies (E14.5) coincides with the generation of pyramidal neurons in layer V in the frontal cortex and in layer VI in the occipital cortex, following the normal rostro-caudal pattern of cortical cell generation. We recently demonstrated that one of the primary antigens recognized by these antibodies corresponds to stress-induced phosphoprotein 1 (STIP1). Here we hypothesize that the reduction in the access of newborn cells to STIP1 in the developing cortex may be responsible for the reduced dendritic arborization and number of spines we noted in the adult cortex.

Behavior of Xeno-Transplanted Undifferentiated Human Induced Pluripotent Stem Cells Is Impacted by Microenvironment Without Evidence of Tumors.

Human pluripotent stem cells (hPSC) have great clinical potential through the use of their differentiated progeny, a population in which there is some concern over risks of tumorigenicity or other unwanted cellular behavior due to residual hPSC. Preclinical studies using human stem cells are most often performed within a xenotransplant context. In this study, we sought to measure how undifferentiated hPSC behave following xenotransplant. We directly transplanted undifferentiated human induced pluripotent stem cells (hIPSC) and human embryonic stem cells (hESC) into the adult mouse brain ventricle and analyzed their fates. No tumors or precancerous lesions were present at more than one year after transplantation. This result differed with the tumorigenic capacity we observed after allotransplantation of mouse ESC into the mouse brain. A substantial population of cellular derivatives of undifferentiated hESC and hIPSC engrafted, survived, and migrated within the mouse brain parenchyma. Within brain structures, transplanted cell distribution followed a very specific pattern, suggesting the existence of distinct microenvironments that offer different degrees of permissibility for engraftment. Most of the transplanted hESC and hIPSC that developed into brain cells were NeuN+ neuronal cells, and no astrocytes were detected. Substantial cell and nuclear fusion occurred between host and transplanted cells, a phenomenon influenced by microenvironment. Overall, hIPSC appear to be largely functionally equivalent to hESC in vivo. Altogether, these data bring new insights into the behavior of stem cells without prior differentiation following xenotransplantation into the adult brain.

Dysregulated iron metabolism in the choroid plexus in fragile X-associated tremor/ataxia syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder associated with premutation alleles of the FMR1 gene that is characterized by progressive action tremor, gait ataxia, and cognitive decline. Recent studies of mitochondrial dysfunction in FXTAS have suggested that iron dysregulation may be one component of disease pathogenesis. We tested the hypothesis that iron dysregulation is part of the pathogenic process in FXTAS. We analyzed postmortem choroid plexus from FXTAS and control subjects, and found that in FXTAS iron accumulated in the stroma, transferrin levels were decreased in the epithelial cells, and transferrin receptor 1 distribution was shifted from the basolateral membrane (control) to a predominantly intracellular location (FXTAS). In addition, ferroportin and ceruloplasmin were markedly decreased within the epithelial cells. These alterations have implications not only for understanding the pathophysiology of FXTAS, but also for the development of new clinical treatments that may incorporate selective iron chelation.