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Abstract
Caspases are a family of conserved cysteine proteases that play key roles in multiple cellular processes, including programmed cell death and inflammation. Recent evidence shows that caspases are also involved in crucial non-apoptotic functions, such as dendrite development, axon pruning, and synaptic plasticity mechanisms underlying learning and memory processes. The activated form of caspase-3, which is known to trigger widespread damage and degeneration, can also modulate synaptic function in the adult brain. Thus, in the present study, we tested the hypothesis that caspase-3 modulates synaptic plasticity at corticostriatal synapses in the phosphatase and tensin homolog (PTEN) induced kinase 1 (PINK1) mouse model of Parkinson’s disease (PD). Loss of PINK1 has been previously associated with an impairment of corticostriatal long-term depression (LTD), rescued by amphetamine-induced dopamine release. Here, we show that caspase-3 activity, measured after LTD induction, is significantly decreased in the PINK1 knockout model compared with wild-type mice. Accordingly, pretreatment of striatal slices with the caspase-3 activator α-(Trichloromethyl)-4-pyridineethanol (PETCM) rescues a physiological LTD in PINK1 knockout mice. Furthermore, the inhibition of caspase-3 prevents the amphetamine-induced rescue of LTD in the same model. Our data support a hormesis-based double role of caspase-3; when massively activated, it induces apoptosis, while at lower level of activation, it modulates physiological phenomena, like the expression of corticostriatal LTD. Exploring the non-apoptotic activation of caspase-3 may contribute to clarify the mechanisms involved in synaptic failure in PD, as well as in view of new potential pharmacological targets.
Highlights
Caspases are a highly conserved family of cysteine proteases playing a central role in the execution phase of apoptotic cell death [1,2]
A further recent electrophysiology study performed on rat hippocampal slices demonstrated that caspase-9-caspase-3 cascade, activated by pro-apoptotic molecules released from mitochondria, is required for the internalization of glutamatergic amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors from synapses and for the induction of long-term depression (LTD) [10]
We previously demonstrated a consistent decrease in evoked dopamine release in PINK1−/− striatal slices by amperometric recordings [22,23]
Summary
Caspases are a highly conserved family of cysteine proteases playing a central role in the execution phase of apoptotic cell death [1,2]. In the healthy adult brain, caspase-3 activity seems essential for physiological synaptic function and neurogenesis [15] Both in vivo and in vitro findings support the involvement of caspase-3 in the molecular mechanisms underlying learning and memory processes [10,16]. We investigated whether caspase-3 plays a role in modulating synaptic plasticity expression at corticostriatal synapses in physiological and pathological conditions. To this aim, we used a well-characterized mouse model of autosomal recessive early-onset Parkinson’s disease (PD) [21], the phosphatase and tensin homolog (PTEN) induced kinase 1 (PINK1) knockout mouse model [22]. We explored whether caspase-3 is involved in the synaptic plasticity machinery underlying the expression of corticostriatal LTD in the PINK1 mouse model
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