Influence of age and strain on striatal dopamine loss in a genetic mouse model of Lesch-Nyhan disease

Lesch-Nyhan disease is a neurogenetic disorder caused by deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) . Affected individuals exhibit a characteristic pattern of neurological and behavioral features attributable in part to dysfunction of basal ganglia d opamine systems. In the current studies, striatal dopamine loss was investi gated in five different HPRT-deficient strains of mice carrying one of two different HPRT gene mutations. Caudoputamen dopamine concentrations were si gnificantly reduced in all five of the strains, with deficits ranging from 50.7 to 61.1%. Mesolimbic dopamine was significantly reduced in only three of the five strains, with a range of 31.6-38.6%. The reduction of caudoputa men dopamine was age dependent, emerging between 4 and 12 weeks of age. Tyr osine hydroxylase and aromatic amino acid decarboxylase, two enzymes respon sible for the synthesis of dopamine, were reduced by 22.4-37.3 and 22.2-43. 1%, respectively. These results demonstrate that HPRT deficiency is strongl y associated with a loss of basal ganglia dopamine. The magnitude of dopa m ine loss measurable is dependent on the genetic background of the mouse str ain used, the basal ganglia subregion examined, and the age of the animals at assessment.