Regional brain variations of cytochrome oxidase activity and motor coordination in Girk2Wv (Weaver) mutant mice

The Girk2Wv (weaver) phenotype, caused by a mutated inward rectifying potassium channel, is characterized by degeneration of cerebellar granule cell population as well as midbrain dopamine-containing cells of the nigrostriatal pathway. To investigate the regional brain metabolic consequences of this combined pathology, cytochrome oxidase (CO) activity was measured by histochemistry from brain regions of wild-type and homozygous Girk2Wv mutant mice and correlated with motor performances. CO activity of Girk2Wv mutants was abnormal in cerebellar cortex, dentate nucleus, and brainstem regions (medial and lateral vestibular nuclei, prepositus, superior colliculus, lateral cuneiform nucleus, and reticular nuclei) implicated in the gaze system. CO activity increased in midbrain dopaminergic regions after correcting for tissue density, regions with severe depletion of tyrosine hydroxylase activity. Forebrain regions were relatively spared in term of CO activity, except for subthalamic nucleus, lateral geniculate nucleus, and cortical eye field. Similarly to the Rorasg cerebellar mutant, metabolic alterations in cerebellar and vestibular regions were linearly correlated with poor motor coordination, underlining the sensitivity of these tests to cerebellar dysfunction.