Abnormalities in neuronal maturation in Rett syndrome neocortex: preliminary molecular correlates

In correspondence with the severe cognitive impairment and autistic features of Rett syndrome (RS), multiple anomalies of the cerebral cortex that include generalized reductions in dendritic arborizations and in cholinergic markers have been found. Considering the potential role of neurotransmitters in cortical differentiation, we have studied the relationship between cholinergic deficit and dendritic protein expression in RS and in a relevant animal model. Dendritic development is characterized by the sequential expression of cytoskeletal proteins whose levels remain relatively stable in adult life. Using quantitative immunoblotting, we have determined that in RS there is a reduction in proteins linked to early dendritic development [microtubule-associated protein (MAP)-5, MAP-2]. By contrast, in Down syndrome there is relative generalized increase in dendritic proteins. Mice with basal forebrain lesions at birth, which transiently decrease cholinergic innervation to the cortex, showed in adulthood reductions in MAP-2 that resemble those seen in RS. We conclude that dendritic anomalies in RS represent disturbances in early cortical differentiation and that cholinergic deficit may play a critical role in their pathogenesis as suggested by the animal data.