A Golgi study of neuronal architecture in a genetic mouse model for Lesch-Nyhan disease

Lesch-Nyhan disease (LND) is an inherited disorder associated with deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT), an enzyme essential for purine recycling. The clinical manifestations of the disorder and several neurochemical studies have pointed towards a defect in the striation, but histological studies of autopsied brain specimens have not revealed any consistent abnormalities. An HPRT-deficient (HPRT-) mouse that has been produced as a model for the disease also exhibits neurochemical abnormalities of the striation without obvious histological correlates. In the current studies, Golgi-Cox histochemistry was used to evaluate the fine structure of medium spiny I neurons from the striation in the HPRT- mice. To determine if any abnormalities might be restricted to striatal neurons, the pyramidal projection neurons of layer 5 of the cerebral cortex were also evaluated. Neurons from both regions demonstrated a normal distribution, orientation, and gross morphology. There was no evidence for an abnormal developmental process or degeneration. However, both regions demonstrated a paucity of neurons with very long dendrites and a reduction in dendritic spines that depended upon the distance from the cell body. These findings demonstrate that HPRT deficiency is associated with changes in neuronal architecture in the HPRT- mice. Similar abnormalities in the LND brain could underlie some of the clinical manifestations. (c) 2005 Elsevier Inc. All rights reserved.