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National security publications November 1, 2013 Conference Paper

Pharmacological Inhibition of Glucocerebrosidase Disrupts Striatal Dopaminergic Neurotransmission

SRI International November 1, 2013

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Mak, S. K., Ko, N., Chou, V. P., Samuelsson, S., Vazquez-Derose, J., & Manning-Bog, A. B. (2013, 9-13 November). Pharmacological inhibition of glucocerebrosidase disrupts striatal dopaminergic neurotransmission. Paper presented at the Neuroscience 2013, San Diego, CA.

Abstract

Clinical, genetic and pathological studies have provided evidence linking Gaucher disease and alpha-synucleinopathies, in particular Parkinson’s disease (PD). To deconstruct the biochemical correlates involved in this association, we evaluated striatal dopaminergic function in a pharmacological model of Gaucher disease using the selective irreversible inhibitor of glucocerebrosidase, conduritol B epoxide (CBE). We have previously shown increased nigral alpha-synuclein associated with glucocerebrosidase inhibition using a single CBE administration to C57BL/6 mice. Here, we utilized a subacute paradigm, exposing animals to 100 mg/kg CBE or vehicle, i.p., once daily for 9 consecutive days. No change in total striatal dopamine levels was detected in mice exposed to CBE or vehicle. However, a marked elevation in GFAP (253%) and an apparent increase Iba-1-positive microglia with activated morphology were observed in striatum from CBE-treated animals. In vivo microdialysis experiments revealed a significant decrease in KCl-evoked striatal DA release in the CBE- vs. vehicle-challenged cohort. Futhermore, electron microscopy revealed a significant reduction in post-synaptic density size (23.5%) in CBE- vs. vehicle-treated striatum, providing further support for the idea that alterations in cellular lipid metabolism contribute to altered neurotransmission and vulnerability in the nigrostriatal pathway. Future studies will further evaluate CBE-induced alterations in pre-synaptic release and post-synaptic complexes and the possibly-related contribution of neuroinflammatory processes on dopaminergic neurotransmission in the model.

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National security publications, Publication Conference Paper

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