Central serotonin system in Dystonia musculorum mutant mice: Biochemical, autoradiographic and immunocytochemical data

The autosomal recessive mutation dystonia musculorum (dt(J)/dt(J)) causes d egenerative alterations of peripheral and central sensory pathways that lea d to ataxia. To investigate possible changes in the central serotonin syste m of these mice, HPLC measurements of 5-hydroxytryptophan, 5-hydroxy-trypta mine (serotonin; 5-HT), and 5-HT metabolites were obtained from 22 brain re gions and the spinal cord of wild type and dt(J)/dt(J) mutant mice. Also, 5 -HT transporters were quantified by [H-3]citalopram autoradiography in 72 b rain regions, subregions, and nuclei, and the 5-HT innervation visualized b y immunocytochemistry throughout the brain and spinal cord. In all brain re gions measured for indoleamine content, there were no significant differenc es between the two genotypes. In the spinal cord, an increased tissue conce ntration of 5-HT (+34%), 5-hydroxyindole-3-acetic acid (+33%), 5-hydroxytry ptophol (+21%), and 5-hydroxytryptophan (+45%) in dt(J)/dt(J) actually corr esponded to the same total amount of each of these indoleamines in the enti re spinal cord, when taking into account its reduced size in the mutants. Q uantification of the binding to 5-HT transporters showed increases in the m edial geniculate nucleus (+14%), medial (+24%) and lateral(+18%) hypothalam us, interpeduncular (+13%) vestibular (+22%), and deep cerebellar nuclei (37%) of dt(J)/dt mice, and decreases in the ventral tegmental area ( -13%), median and linear raphe nuclei (-20%), as well as in the solitary complex (-35%). There were no apparent differences in the distribution of 5-HT-immu nostained fibers in these and other regions of brain and in the spinal cord of dt(J)/dt(J) compared to wild type mice. The bulk of these results indic ates a relative sparing of the central 5-HT system in the dt(J)/dt(J) mice, even though alterations in 5-HT transporters could justify attempts at imp roving the sensorimotor dysfunction by administration of serotoninergic age nts in these mice. Synapse 37:179-193, 2000. (C) 2000 Wiley-Liss, Inc.