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J. Biol. Chem., Vol. 280, Issue 52, 42508-42514, December 30, 2005

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High Resolution ¹H NMR-based Metabolomics Indicates a Neurotransmitter Cycling Deficit in Cerebral Tissue from a Mouse Model of Batten Disease^*

Michael R. Pears1, Jonathan D. Cooper, Hannah M. Mitchison¶, Russell J. Mortishire-Smith||, David A. Pearce**, and Julian L. Griffin2

From the Department of Biochemistry, Tennis Court Road, University of Cambridge, Cambridge CB2 1GA, United Kingdom, the Pediatric Storage Disorders Laboratory, Department of Neuroscience, Medical Research Council Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, De Crespigny Park, London SE5 8AF, United Kingdom, the ^¶Department of Paediatrics and Child Health, Royal Free and University College Medical School, Rayne Building, University Street, London WC1E 6JJ, United Kingdom, the ^||Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, United Kingdom, and the ^**Center for Aging and Developmental Biology, Aab Institute of Biomedical Sciences, Department of Biochemistry and Biophysics and Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

The neuronal ceroid lipofuscinoses (NCLs) constitute a range of progressive neurological disorders primarily affecting children. Although six of the causative genes have been characterized, the underlying disease pathogenesis for this family of disorders is unknown. Using a metabolomics approach based on high resolution ¹H NMR spectroscopy of the cortex, cerebellum, and remaining regions of the brain in conjunction with statistical pattern recognition, we report metabolic deficits associated with juvenile NCL in a Cln3 knock-out mouse model. Tissue from Cln3 null mutant mice aged 1–6 months was characterized by an increased glutamate concentration and a decrease in -amino butyric acid (GABA) concentration in aqueous extracts from the three regions of the brain. These changes are consistent with the reported altered expression of genes involved in glutamate metabolism in older mice and imply a change in neurotransmitter cycling between glutamate/glutamine and the production of GABA. Further variations in myo-inositol, creatine, and N-acetyl-aspartate were also identified. These metabolic changes were distinct from the normal aging/developmental process. Together, these changes represent the first documented pre-symptomatic symptoms of the Cln3 mouse at 1 month of age and demonstrate the versatility of ¹H NMR spectroscopy as a tool for phenotyping mouse models of disease.

Received for publication, July 7, 2005 , and in revised form, September 2, 2005.

^* This work was supported in part by National Institutes of Health Metabolomics Roadmap Initiative Grant R21DK070288-01 and Commission of the European Communities Grant 503051. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a Biotechnology and Biological Sciences Research Council Cooperative Awards in Science and Engineering (CASE)-sponsored studentship in conjunction with Merck Sharp and Dohme.

² Grateful recipient of a University Research Fellowship from the Royal Society and to whom correspondence should be addressed. Tel.: 44-1223-333626; Fax: 44-1223-766002; E-mail: jlg40{at}mole.bio.cam.ac.uk.

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