Loss of Non-Apoptotic Role of Caspase-3 in the PINK1 Mouse Model of Parkinson's Disease

Paola Imbriani, Annalisa Tassone, Maria Meringolo, Giulia Ponterio, Graziella Madeo, Antonio Pisani, Paola Bonsi, Giuseppina Martella, Paola Imbriani, Annalisa Tassone, Maria Meringolo, Giulia Ponterio, Graziella Madeo, Antonio Pisani, Paola Bonsi, Giuseppina Martella

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.

Keywords: PINK1; Parkinson’s disease; caspase-3; long-term depression; striatum; synaptic plasticity.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Intrinsic membrane properties of medium spiny neurons (MSNs) in phosphatase and tensin homolog (PTEN) induced kinase 1 (PINK1) mice after pretreatment with caspase-3 inhibitor and caspase-3 activator. (A) Superimposed traces showing voltage responses to current steps in both hyperpolarizing (−200 pA, 80 ms) and depolarizing (+400 pA, 80 ms) direction from PINK1+/+ (black trace), PINK1+/− (red trace), and PINK1−/− (blue trace) MSNs. No significant differences were observed between the three genotypes. (B) Representative single action potentials recorded from MSNs both in basal condition and after treatment with the caspase-3 inhibitor Z-Devd-fmk (5 µM) or with the caspase-3 activator α-(Trichloromethyl)-4-pyridineethanol (PETCM 30 µM) in all PINK1 genotypes. We did not observe significant differences between groups, in terms of upward spike, firing threshold, and half amplitude duration. (C–F) Whisker plots showing (C) action potential amplitude (PINK1+/+: 77.00 ± 3.8 mV; PINK1+/−: 78.4 ± 3.6 mV; PINK1−/−: 79.4 ± 4.02 mV; n = 9 for each group; one-way analysis of variance (ANOVA) p > 0.05), (D) delay to first spike (PINK1+/+: 40.65 ± 1.99 ms; PINK1+/−: 42.13 ± 1.6 ms; PINK1−/−: 44.23 ± 2.01 ms; n = 9 for each group; one-way ANOVA p > 0.05), (E) resting membrane potential (RMP) (PINK1+/+: −85 ± 3.8 mV; PINK1+/−: −87.21 ± 3.6 mV; PINK1−/−: −79.4 ± 4.02 mV; n = 9 for each group; one-way ANOVA; RMP Z-Dved-fmk on PINK1+/+: −90.53 ± 1.59 mV; Z-Dved-fmk on PINK1+/−: −88.51 ±1.60 mV; Z-Dved-fmk on PINK1−/−: −87.10 ± 3.1 mV; n = 9 for each group; two-way ANOVA p > 0.05), and (F) Rheobase (PINK1+/+: 4201 ± 12.1 ms; PINK1+/−: 400 ± 18.1 ms; PINK1−/−: 380 ± 18 ms; n = 9 for each group; one-way ANOVA p > 0.05) values, without significant differences between genotypes, regardless of treatment with caspase-3 inhibitor/activator.
Figure 2
Figure 2
Pretreatment with caspase-3 inhibitor and activator does not affect evoked synaptic responses in PINK1 MSNs. Stimulation of corticostriatal fibers in the presence of Picrotoxin (PTX, 50 µM) produced glutamatergic excitatory postsynaptic potentials (EPSPs). Input–output (I/O) curves were built by measuring the amplitude of EPSPs evoked by increasing intensities of stimulation. (A) The I/O relationships were not significantly different between the three PINK1 genotypes. The inset shows representative superimposed traces of a single recording. (B) Treatment with PETCM (30 µM) did not induce significant differences neither among the three genotypes nor as compared with non-treated MSNs. (C) Similarly, treatment with Z-Devd-fmk (5 µM) did not affect the I/O curves in any experimental condition. (D) Plots showing EPSP slope values recorded from PINK1+/+ (black), PINK1+/− (red), and PINK1−/− (blue) MSNs treated with vehicle, PETCM, or Z-Devd-fmk. No significant differences were observed among groups (50 µA stimulus: PINK1+/+: 3.84 ± 0.27 mV/ms, n = 11; PINK1+/−: 3.5 ± 0.66 mV/ms, n = 10; PINK1−/−: 3.6 ± 0.3 mV/ms, n = 10; PINK1+/+ in Z-Devd-fmk: 4.21 ± 0.3 mV/ms, n = 10; PINK1+/− in Z-Devd-fmk: 4.8 ± 0.61 mV/ms, n = 10; PINK1−/− in Z-Devd-fmk: 4.01 ± 0.72 mV/ms, n = 8; PINK1+/+ in PETCM: 4.4 ± 0.6 mV/ms, n = 8; PINK1+/− in PETCM: 4.78 ± 1.02 mV/ms, n = 7; PINK1−/− in PETCM: 4.21 ± 0.53 mV/ms, n = 8; two-way ANOVA p > 0.05). (E,F) Paired-pulse facilitation (50 ms ISI) was similar in all PINK1 genotypes, both in saline solution and after pharmacological treatment. (E) The plot shows paired-pulse ratio (PPR) values, defined as EPSP2/EPSP1 ratio (PPR: PINK1+/+: 1.2 ± 0.16, n = 6; PINK1+/−: 1.23 ± 0.14, n = 6; PINK1−/−: 1.28 ± 0.12, n = 6; PINK1+/+ in Z-Devd-fmk: 1.28 ± 0.12, n = 9; PINK1+/+ in PETCM: 1.2 ± 0.10, n = 9; PINK1+/− in Z-Devd-fmk: 1.32 ± 0.02, n = 9; PINK1+/− in PETCM: 1.30 ± 0.16, n = 9; two-way ANOVA p > 0.05). (F) Representative paired recordings of EPSPs from PINK1−/− MSNs after treatment with saline solution (a, black traces), PETCM (b, red traces), and Z-Devd-fmk (c, blue traces) (PPR: PINK1−/− in saline: 1.32 ± 0.10, n = 9; PINK1−/− in Z-Devd-fmk: 1.25 ± 0.14, n = 9; PINK1−/− in PETCM: 1.32 ± 0.10, n = 9; one-way ANOVA p > 0.05).
Figure 3
Figure 3
Long-term depression (LTD) in PINK1+/+ and PINK1+/− mice is suppressed by caspase-3 inhibition. (A,B) Top. Time-course of LTD in PINK1+/+ and PINK1+/− mice. Stimulus intensity was raised to reach threshold level for high-frequency stimulation (HFS). The amplitude of EPSPs was plotted over-time as percentage of the pre-HFS control EPSP. (A) HFS of corticostriatal glutamatergic afferents elicited a robust LTD in MSNs recorded from PINK1+/+ mice (black dots), but not after pretreatment with the caspase-3 inhibitor Z-Dved-fmk (5 µM) (white dots) (PINK1+/+ in Z-Devd-fmk: 98.25% ± 2.12% of control, n = 8; Student’s t-test p > 0.05; PINK1+/+ in saline: 63.70% ± 3.09% of control, n = 6; Student’s t-test p < 0.05). (B) Similarly, Z-Dved-fmk treatment suppressed LTD expression in PINK1+/− mice (PINK1+/− in Z-Devd-fmk: 105.69% ± 3.0% of control, n = 8, Student’s t-test p > 0.05; PINK1+/− in saline: 61.44% ± 1.28% of control, n = 10; Student’s t-test p < 0.05). Each data point represents the mean ± SEM of eight independent observations for each group. Bottom. Sample traces of representative EPSPs recorded before (pre) and 30 min after (post) HFS in PINK1+/+ and PINK1+/− mice, both in control condition and after treatment with Z-Dved-fmk. (C) Plot summarizing corticostriatal LTD expression in PINK1 mice. (D) The plot summarizes the loss of corticostriatal LTD after Z-Dved-fmk treatment in PINK1+/+ and PINK1+/− genotypes.
Figure 4
Figure 4
Long-term depression impairment in PINK1−/− MSNs is rescued by caspase-3 activation. (A,B) Top. Time-course of LTD in PINK1−/− mice. (A) HFS-protocol did not elicit LTD in MSNs recorded from PINK1−/− mice (blue dots), but induced the expression of physiological LTD after pretreatment with the caspase-3 activator PETCM (30 µM) (empty dots) (PINK1−/− in PETCM: 61.63% ± 1.40% of control, n = 8; Student’s t-test p < 0.05; PINK1−/− in saline: 98.55% ± 2.7.% of control, n = 6; Student’s t-test p > 0.05). (B) Treatment whit amphetamine (100 µM) was also able to rescue LTD in PINK1−/− mice (dark blue dots). However, combined treatment with amphetamine plus Z-Dved-fmk failed to rescue LTD in the same PINK1 genotype (green dots) (PINK1−/− in amphetamine: 60.15% ± 3.67% of control, n = 6; Student’s t-test p < 0.05; PINK1−/− in Z-Devd-fmk + amphetamine: 101% ± 3.08% of control, n = 6; Student’s t-test p > 0.05). Bottom. Sample traces of representative EPSPs recorded before (pre) and 30 min after (post) HFS in PINK1−/− mice, in all the described experimental conditions. (C,D) The plots summarize the rescue of corticostriatal LTD after either PETCM or amphetamine treatment and the loss of LTD after combined treatment with amphetamine plus Z-Dved-fmk in PINK1−/− mice.
Figure 5
Figure 5
Caspase-3 biochemical assay showed low levels of caspase-3 in PINK1−/− mice after HFS. Non-treated (CTL) brain slices obtained from the three genotypes did not show significant differences in caspase-3 activity levels (PINK1+/+: absorbance = 0.048 ± 0.023, n = 6; black column; PINK1+/−: absorbance = 0.052 ± 0.007, n = 3; red column; PINK1−/−: absorbance = 0.057 ± 0.020, n = 6; blue column; one-way ANOVA and Tukey post hoc test, p > 0.05). Caspase-3 activity measured post-HFS was significantly reduced in PINK1−/− slices compared with other genotypes (PINK1+/+: absorbance = 0.070 ± 0.017, n = 6; black column; PINK1+/−: absorbance = 0.061 ± 0.017, n = 3; red column; PINK1−/−: absorbance = 0.042 ± 0.010, n = 5; blue column; one-way ANOVA and Tukey post hoc test, *p < 0.05). If slices were pretreated with the activator of caspase-3, PETCM, the same HFS protocol induced similar levels of caspase-3 activity (PINK1+/+: absorbance = 0.070 ± 0.015, n = 6; black column; PINK1+/−: absorbance = 0.066 ± 0.006, n = 3; red column; PINK1−/−: absorbance = 0.064 ± 0.008, n = 6; blue column; one-way ANOVA and Tukey post hoc test, p > 0.05). Data are represented as mean ± SD.
Figure 6
Figure 6
Effect of caspase-3 activation on synaptic responses to sustained electrical stimulation in PINK1−/− MSNs. (A) Time-course of synaptic responses to sustained stimulation (30 Hz, 30 s) in PINK1+/+ MSNs. Current peak amplitudes are reported as mean ± SEM. In the inset, the first and last EPSC from a representative experiment are shown. (B) Time course of synaptic responses in PINK1+/− MSNs shows a similar response to sustained stimulation. (C) In PINK−/− MSNs, we observed a faster depression kinetics after the 12th stimulus. (D) In PINK1+/+ MSNs, the normalized current curve shows an initial fast depression, followed by a slow fall of response. The fit was used to measure the time constant of synaptic depression, which appeared slightly different in PINK1−/− mice compared with PINK1+/+ and PINK1+/− mice. Decay time constants: PINK1+/+: 18.88 ± 0.8 ms, n = 4; PINK1+/−: 18.68 ± 0.56 ms, n = 5; PINK1−/−: 12,43 ± 2.43 ms, n = 6; ANOVA and Tukey post hoc, p < 0.05). (E) Time-course of synaptic responses to sustained stimulation in the presence of amphetamine (100 µM) (blue) and PETCM (30 µM) (gray). No significant differences were observed among the three genotypes when PINK1−/− was treated by either amphetamine. (F) No differences were detected between normalized curves obtained from PINK1−/− MSNs treated with either amphetamine or PETCM. Time constants: PINK1−/− plus amphetamine: 19.28 ± 0.93 ms, n = 6; p > 0.05 vs. PINK1−/−; PINK1−/− plus PETCM: 17.22 ± 0.86 ms, n = 4; p > 0.05 vs. PINK1−/−.

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