Objective: We set out to investigate whether caspase-3 plays a role in the loss of dendritic spines and the concomitant synaptic deficits that develop in striatal spiny projection neurons (SPNs) with the loss of dopaminergic innervation.

Background: Caspases are cysteine proteases mediating apoptosis. However, accumulating evidence show that caspases also fulfill non-apoptotic roles in both neurons and glial cells. Studies in hippocampal neurons have shown that caspase-3 can mediate pruning of axons, dendrites and spines in the absence of cell death. Loss of dendritic spines is prominent in striatal neurons in Parkinson´s disease (PD). Studies in animal models have revealed that SPNs forming the indirect pathways (iSPNs) are particularly affected, but the molecular mediators of iSPN dendritic remodeling are poorly understood.

Method: 6-hydrodydopamine (6-OHDA) was injected unilaterally in the medial forebrain bundle (MFB) in mice, obtaining a parkinsonian model with clinically relevant motor deficits. One group of mice received systemic treatment with the pan-caspase inhibitor, Q-VD-QPh, for five consecutive days starting on the day after lesion surgery. Two-photon laser scanning microscopy was used to study iSPN dendritic morphology in corticostriatal slices. High-frequency stimulation of corticostriatal afferents was applied to induce long-term depression (LTD) of synaptic transmission onto iSPNs.

Results: At 5 days post 6-OHDA lesion, there was a significant striatal upregulation of caspase-3 in both glial cells and iSPN dendrites, which gradually declined until 28 days post lesion. There was however no biochemical or morphological sign of apoptosis in the striatum. At 5 days post lesion, iSPNs showed reduced spine density and an inability to form corticostriatal LTD. Treatment with Q-VD-OPh prevented the loss of dendritic spines and rescued LTD in iSPNs without interfering with the 6-OHDA-induced dopaminergic degeneration.

Conclusion: Our study is the first to link spine loss and early synaptic dysfunction of dopamine-denervated iSPNs to non-apoptotic caspase-3 activation. We are now investigating the underlying molecular pathways.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/non-apoptotic-caspase-3-activation-mediates-early-synaptic-dysfunction-of-indirect-pathway-neurons-in-the-parkinsonian-striatum/