NEUROBIOLOGY OF RETT-SYNDROME

From a neurobiologic perspective, Rett syndrome appears to disrupt the growth of axonodendritic connections among neurons. The cell packing density within the grey matter is increased but the total number of neurons is relatively normal, except for selected neuronal populations such as the nucleus basalis of Meynert (NBM) and the substantia nigra. Neurochemical assays of postmortem brain from patients with Rett syndrome patients demonstrate reductions in choline acetyltransferase (ChAT), the acetylcholine synthetic enzyme localized in NBM nerve terminals. In an animal model, early postnatal injury to the cholinergic pathways projected from the NBM causes permanent disruption of developing cholinergic neurons and a behavioral disorder on maze testing. The results suggest a mechanism by which early deficits in cholinergic and dopamine neurons projecting to the cerebral cortex from the brainstem and basal forebrain could disrupt axonodendritic development in the cerebral cortex. Studies in our laboratory are examining the mechanisms for these effects as well as the distribution and densities of neurotransmitter receptors in postmortem brains from Rett patients.