Alterations in synaptic connectivity in cerebral cortex in neuronal storage disorders

Neuronal storage diseases are inborn errors of metabolism characterized by widespread intraneuronal storage and progressive neurological dysfunction, including mental retardation, movement disorders, and seizures. Most of these disorders are associated with specific defects in particular lysosomal enzymes. Moreover, a wide array of genetic defects has been documented. The immense progress made during the past three decades in understanding the primary molecular and enzymatic defects in this family of diseases stands in sharp contrast to the modest advances made in delineating pathogenetic mechanisms and treatment strategies. Although these disorders result from highly selective defects in metabolic pathways, they ultimately are complex conditions characterized by a plethora of seemingly unrelated secondary molecular and cellular abnormalities. Studies of children and animals affected by these diseases have revealed that significant changes in neuronal connectivity occur in the cerebral cortex. These include not only degenerative changes in axons and synapses of inhibitory neurons, but also a regrowth of dendrites and new synapse formation involving pyramidal neurons. The latter finding indicates that neurons in the cerebral cortex undergo significant “rewiring” during the height of the disease process. This regrowth of primary dendrites and formation of new synapses as part of a neurological disease is unprecedented. Understanding the causes and consequences of these changes in cortical synaptic connectivity in neuronal storage diseases may provide insight not only into the precise mechanisms underlying mental retardation in these diseases and their reversibility, but also into processes governing dendritic elaboration and synapse formation in the normal developing nervous system. © 1995 Wiley-Liss, Inc.