Pharmacological Inhibition of Glucocerebrosidase Disrupts Striatal Dopaminergic Neurotransmission

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.