AAV-BDNF mediated attenuation of quinolinic acid-induced neuropathology and motor function impairment.
Maintenance and plasticity of striatal neurons is dependent on brain-derived neurotrophic factor (BDNF), which is depleted in the Huntington's disease striatum due to reduced expression and disrupted corticostriatal transportation. In this study we demonstrate that overexpression of BDNF in the striatum attenuates motor impairment and reduces the extent of striatal damage following quinolinic acid lesioning. Transfer of the BDNF gene to striatal neurons using serotype 1/2 adeno-associated viral vectors enhanced BDNF protein levels in the striatum, but induced weight loss and seizure activity following long-term high-level expression. Lower concentration BDNF expression supported striatal neurons against excitotoxic insult, as demonstrated by enhanced krox-24 immunopositive neuron survival, reduction of striatal atrophy and maintenance of the patch/matrix organization. Additionally, BDNF expression attenuated motor impairment in the forelimb use cylinder test, sensorimotor neglect in the corridor food selection task and reversed apomorphine-induced rotational behaviour. Direct correlations were shown for the first time between BDNF-mediated attenuation of behavioural impairment and the integrity of the globus pallidus, seemingly independent from the severity of striatal lesioning. These results demonstrate that BDNF holds considerable therapeutic potential for alleviating both neuropathological and motor function deficits in the Huntington's disease brain, and the critical role of pallidal neurons in facilitating motor performance.
Kells
A P
AP
Department of Pharmacology and Clinical Pharmacology, Neural Repair and Neurogenesis Laboratory, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Henry
R A
RA
Connor
B
B
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D003342:Corpus Striatum / Q000737:chemistry / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006816:Huntington Disease / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D007150:Immunohistochemistry; D007267:Injections; D008297:Male; D023421:Models, Animal; D009043:Motor Activity; D009474:Neurons / Q000378:metabolism*; D017378:Quinolinic Acid; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D014161:Transduction, Genetic / Q000379:methods
D019208:Brain-Derived Neurotrophic Factor; D017378:Quinolinic Acid