Morphological Study of the Entorhinal Cortex, Hippocampal Formation, and Basal Ganglia in Rett Syndrome Patients

Leontovich, T. A.; Mukhina, Julia K.; Fedorov, A.A.; Belichenko, Pavel V.

doi:10.1006/nbdi.1998.0234

Cited by 25 publications

(21 citation statements)

References 62 publications

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“…Histological changes in hippocampal formation, entorhinal cortex and basal ganglia systems in RTT (Leontovich et al, 1999) correlate with our data on significant reduction of hippocampal and cortical volumes in both Mecp2-mutant mice, with reduced areas of fornix and fimbria in Mecp2B mice, and with published data on striatum (Stearns et al, 2007). Significant changes in hippocampal volume may reflect a dramatic reduction in LTP, seen in both Mecp2-mutant mice (Asaka et al, 2006) and changes in behavior (Stearns et al, 2007).…”

Section: Differences In Severity In Brain Morphology Of Mecp2b and Mesupporting

confidence: 90%

“…In contrast, measurements of CC, PC, and MTT showed reductions in the mutants that were not statistically significant. Taken together, these data and previously published results on human RTT brain studies (Belichenko et al, 1994;Leontovich et al, 1999) point to heavy involvement of axonal connections in the pathogenesis of RTT.…”

Section: Differences In Severity In Brain Morphology Of Mecp2b and Mesupporting

confidence: 82%

“…A recent detailed study of neuronal cell body and axonal fiber morphology showed involvement of the entorhinal cortex, hippocampal formation, and basal ganglia (Leontovich et al, 1999). Taking the intensity of cresyl violet staining in individual neurons as a marker of activity, both increases and decreases were detected (Leontovich et al, 1999). Corpus callosum widths were significantly reduced in RTT subjects (Murakami et al, 1992;Reiss et al, 1993).…”

mentioning

confidence: 97%

“…Afferent fibers to spines and the axonal bundles in which they traveled were disorganized in the cortex of RTT subjects (Belichenko et al, 1994). A recent detailed study of neuronal cell body and axonal fiber morphology showed involvement of the entorhinal cortex, hippocampal formation, and basal ganglia (Leontovich et al, 1999). Taking the intensity of cresyl violet staining in individual neurons as a marker of activity, both increases and decreases were detected (Leontovich et al, 1999).…”

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confidence: 98%

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Comparative study of brain morphology in Mecp2 mutant mouse models of Rett syndrome

Belichenko

et al. 2008

J of Comparative Neurology

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Rett syndrome (RTT) is caused by mutations in the X-linked gene MECP2. While patients with RTT show widespread changes in brain function, relatively few studies document changes in brain structure and none examine in detail whether mutations causing more severe clinical phenotypes are linked to more marked changes in brain structure. To study the influence of MeCP2-deficiency on the morphology of brain areas and axonal bundles, we carried out an extensive morphometric study of two Mecp2-mutant mouse models (Mecp2B and Mecp2J) of RTT. Compared to wildtype littermates, striking changes included reduced brain weight ( approximately 13% and approximately 9%) and the volumes of cortex ( approximately 11% and approximately 7%), hippocampus (both by approximately 8%), and cerebellum ( approximately 12% and 8%) in both mutant mice. At 3 weeks of age, most (24 of 47) morphological parameters were significantly altered in Mecp2B mice; fewer (18) were abnormal in Mecp2J mice. In Mecp2B mice, significantly lower values for cortical area were distributed along the rostrocaudal axis, and there was a reduced length of the olfactory bulb ( approximately 10%) and periaqueductal gray matter ( approximately 16%). In Mecp2J mice, while there was significant reduction in rostrocaudal length of cortex, this parameter was also abnormal in hippocampus ( approximately 10%), periaqueductal gray matter ( approximately 13%), fimbria ( approximately 18%), and anterior commissure ( approximately 10%). Our findings define patterns of Mecp2 mutation-induced changes in brain structure that are widespread and show that while some changes are present in both mutants, others are not. These observations provide the underpinning for studies to further define microarchitectural and physiological consequences of MECP2 deficiency.

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Section: Differences In Severity In Brain Morphology Of Mecp2b and Mesupporting

confidence: 90%

Section: Differences In Severity In Brain Morphology Of Mecp2b and Mesupporting

confidence: 82%

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confidence: 97%

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confidence: 98%

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Comparative study of brain morphology in Mecp2 mutant mouse models of Rett syndrome

Belichenko

et al. 2008

J of Comparative Neurology

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“…Such alterations could explain both our findings of increased numbers of hyperchromic, tightly packed but TUNEL-negative pyramidal neurons in CA1 and CA2, as well as the generalized enlargement of hippocampal structures. These findings are reminiscent of Rett syndrome, a disorder with clinical features overlapping with those of autism but caused by mutations in the X-linked methyl-CpG-binding protein 2, 60 where CA1 pyramidal neurons of increased cell packing density, without evidence of active degeneration 61 and with hyperchromic appearance, 62 are reported. Age-associated brain overgrowth is also noted in autism.…”

Section: Discussionmentioning

confidence: 94%

Neurotoxic effects of postnatal thimerosal are mouse strain dependent

2004

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The developing brain is uniquely susceptible to the neurotoxic hazard posed by mercurials. Host differences in maturation, metabolism, nutrition, sex, and autoimmunity influence outcomes. How population-based variability affects the safety of the ethylmercury-containing vaccine preservative, thimerosal, is unknown. Reported increases in the prevalence of autism, a highly heritable neuropsychiatric condition, are intensifying public focus on environmental exposures such as thimerosal. Immune profiles and family history in autism are frequently consistent with autoimmunity. We hypothesized that autoimmune propensity influences outcomes in mice following thimerosal challenges that mimic routine childhood immunizations. Autoimmune disease-sensitive SJL/J mice showed growth delay; reduced locomotion; exaggerated response to novelty; and densely packed, hyperchromic hippocampal neurons with altered glutamate receptors and transporters. Strains resistant to autoimmunity, C57BL/ 6J and BALB/cJ, were not susceptible. These findings implicate genetic influences and provide a model for investigating thimerosal-related neurotoxicity.

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Widespread changes in dendritic and axonal morphology in Mecp2‐mutant mouse models of rett syndrome: Evidence for disruption of neuronal networks

Belichenko¹,

Wright²,

Belichenko³

et al. 2009

J of Comparative Neurology

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257

190

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Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked gene MECP2. Girls with RTT show dramatic changes in brain function, but relatively few studies have explored the structure of neural circuits. Examining two mouse models of RTT (Mecp2B and Mecp2J), we previously documented changes in brain anatomy. Herein, we use confocal microscopy to study the effects of MeCP2 deficiency on the morphology of dendrites and axons in the fascia dentata (FD), CA1 area of hippocampus, and motor cortex following Lucifer yellow microinjection or carbocyanine dye tracing. At 3 weeks of age, most (33 of 41) morphological parameters were significantly altered in Mecp2B mice; fewer (23 of 39) were abnormal in Mecp2J mice. There were striking changes in the density and size of the dendritic spines and density and orientation of axons. In Mecp2B mice, dendritic spine density was decreased in the FD (approximately 11%), CA1 (14-22%), and motor cortex (approximately 16%). A decreased spine head size (approximately 9%) and an increased spine neck length (approximately 12%) were found in Mecp2B FD. In addition, axons in the motor cortex were disorganized. In Mecp2J mice, spine density was significantly decreased in CA1 (14-26%). In both models, dendritic swelling and elongated spine necks were seen in all areas studied. Marked variation in the type and extent of changes was noted in dendrites of adjacent neurons. Electron microscopy confirmed abnormalities in dendrites and axons and showed abnormal mitochondria. Our findings document widespread abnormalities of dendrites and axons that recapitulate those seen in RTT.

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Morphological Study of the Entorhinal Cortex, Hippocampal Formation, and Basal Ganglia in Rett Syndrome Patients

Cited by 25 publications

References 62 publications

Comparative study of brain morphology in Mecp2 mutant mouse models of Rett syndrome

Comparative study of brain morphology in Mecp2 mutant mouse models of Rett syndrome

Neurotoxic effects of postnatal thimerosal are mouse strain dependent

Widespread changes in dendritic and axonal morphology in Mecp2‐mutant mouse models of rett syndrome: Evidence for disruption of neuronal networks

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