298 Metabolic and Glutamatergic Disturbances in the Huntington’s Disease Transgenic Mouse DONALD S. HIGGINS, a KARI R. HOYT, CORINNE BAIC, JESSICA VENSEL, AND MATTHEW SULKA Departments of Neurology, and Cell Biology, Neurobiology and Anatomy The Ohio State University, Columbus, Ohio 43210, USA Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by involuntary movements, mood disturbance and dementia. Excito- toxicity appears to play an essential role in striatal projection neuron degeneration. Accumulating evidence suggests augmentation of neuronal injury by metabolic dys- function. 1 Inefficient ATP synthesis will compromise the resting membrane poten- tial and induce aberrant glutamate receptor activation and excitotoxic neuronal injury. Recently, the trinucleotide repeat expansion accounting for autosomal dominant inheritance has been inserted into the laboratory mouse. 2 This transgenic strain (R6/2) has provided a valuable tool with which to investigate the pathogenesis of HD. We have examined, using enzyme histochemistry and receptor autoradiography, the integrity of oxidative metabolism, intermediary metabolism and ionotropic glutamate receptors in brain of this strain and wildtype controls (n = 4/group). Transgenic animals were significantly smaller than nontransgenic animals at 8 weeks of age (24.6 g vs. 30.1 g, p = 0.008). Metabolic and receptor alterations were evident in all brain regions examined (TABLE 1). A generalized reduction (-42.7– 58.8%) in lactate dehydrogenase (LDH) activity was observed in transgenic animals. Disturbances of lactate metabolism have been reported in HD. 3 Reduced LDH activ- ity may represent the enzymatic correlate of cerebral lactic acidosis. [ 3 H]Dihydroro- tenone binding to complex I of the electron transport chain was increased in striatum (+14.5%, p = 0.04) and molecular layer of the cerebellum (+10.8%, p = 0.008) of the HD transgenic mice. Decreased complex I activity has been reported in HD plate- lets. 4 Increased complex I protein may reflect compensation for impaired function. Abnormalities of complex II/III and complex IV have been previously described in HD 5,6 and recently in the R6/2 line. 7 While no change was observed in the current experiments, the optimized histochemical methods used to visualize cytochrome ox- idase (complex IV) and succinate dehydrogenase (complex II) may have obscured subtle, yet physiologically relevant, changes in these enzymes. Phosphate-activated glutaminase (PAG) plays a crucial role in transmitter glutamate metabolism. Increased striatal PAG activity (+30.0%, p = 0.004) in the transgenic mice may reflect an increase in synaptic glutamate. In accord with this a Address for correspondence: Donald S. Higgins, Jr., MD, The Ohio State University, 188 Medical Research Facility, 420 West 12th Ave., Columbus, OH 43210. Phone: 614-688-4048; fax: 614-688-8755. e-mail: higgins.84@osu.edu