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

Abstract

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.

Synaptic Dysfunction in Neurodevelopmental Disorders Associated with Autism and Intellectual Disabilities

“…Despite the devastating neurological phenotypes, the brain appears normal, with the exception of microcephaly, decrease in dendritic spine density, and dendritic swelling (Belichenko et al 2009). Mice expressing twice the normal levels of MeCP2 reproduce human duplication syndrome features, but without much evidence of major pathological changes (Collins et al 2004).…”

A review of Rett syndrome (RTT) with induced pluripotent stem cells

“…The regulation of protein synthesis via the PI3K pathway has been proven to be crucial in synaptic function, dendrite structure, and plasticity (74)(75)(76). All of these functions have been shown to be compromised in RTT (77,78). Recently, direct evidence has demonstrated the dysregulation of the entire Akt/mTOR axis in MeCP2 null mice, giving a molecular theoretical framework for the mechanism of action of genes regulated by MeCP2, like BDNF (79).…”

Bridging the Gap between Genes and Behavior: Brain-Derived Neurotrophic Factor and the mTOR Pathway in Idiopathic Autism

“…Both up-and down-regulation of the mTOR pathway result in abnormal spine morphology and density as seen in tuberous sclerosis complex (increased mTOR), fragile X (increased mTOR) and Rett (decreased mTOR) syndrome animal models and patients [112]. Specifically, both tuberous sclerosis complex and Rett syndrome are characterized by a decreased number of spines, with the spines that are present having elongated necks [119][120][121][122]. However, spine heads are enlarged in tuberous sclerosis complex [119], while they are reduced in Rett syndrome [121].…”

“…Specifically, both tuberous sclerosis complex and Rett syndrome are characterized by a decreased number of spines, with the spines that are present having elongated necks [119][120][121][122]. However, spine heads are enlarged in tuberous sclerosis complex [119], while they are reduced in Rett syndrome [121]. Lastly, patients and rodent models of fragile X syndrome have an increased density of long and thin (immature) spines [123][124][125][126][127].…”