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. 2007 Jul 3;104(27):11441-6.
doi: 10.1073/pnas.0702717104. Epub 2007 Jun 11.

Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice

Tohru Kitada  1 , Antonio Pisani, Douglas R Porter, Hiroo Yamaguchi, Anne Tscherter, Giuseppina Martella, Paola Bonsi, Chen Zhang, Emmanuel N Pothos, Jie Shen
Affiliations

Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice

Tohru Kitada et al. Proc Natl Acad Sci U S A. .

Abstract

Parkinson's disease (PD) is characterized by the selective vulnerability of the nigrostriatal dopaminergic circuit. Recently, loss-of-function mutations in the PTEN-induced kinase 1 (PINK1) gene have been linked to early-onset PD. How PINK1 deficiency causes dopaminergic dysfunction and degeneration in PD patients is unknown. Here, we investigate the physiological role of PINK1 in the nigrostriatal dopaminergic circuit through the generation and multidisciplinary analysis of PINK1(-/-) mutant mice. We found that numbers of dopaminergic neurons and levels of striatal dopamine (DA) and DA receptors are unchanged in PINK1(-/-) mice. Amperometric recordings, however, revealed decreases in evoked DA release in striatal slices and reductions in the quantal size and release frequency of catecholamine in dissociated chromaffin cells. Intracellular recordings of striatal medium spiny neurons, the major dopaminergic target, showed specific impairments of corticostriatal long-term potentiation and long-term depression in PINK1(-/-) mice. Consistent with a decrease in evoked DA release, these striatal plasticity impairments could be rescued by either DA receptor agonists or agents that increase DA release, such as amphetamine or l-dopa. These results reveal a critical role for PINK1 in DA release and striatal synaptic plasticity in the nigrostriatal circuit and suggest that altered dopaminergic physiology may be a pathogenic precursor to nigrostriatal degeneration.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Normal dopaminergic neurons and DA levels in PINK1−/− mice. (A) Targeting strategy. The KpnI (K)-Bsr GI (B) fragment containing exon 3 is used as the 5′ homologous region. P1 and P2 represent the positions of the primers used to amplify the 3′ homologous region that contains exon 8. The 3′ probe indicates the position of the 3′ external probe used to screen for targeted ES cells carrying the proper recombination in the 3′ homologous region. P3 and P4 are the primers used to confirm the correct recombination in the 5′ homologous region. E, EcoRV; K, KpnI; B, Bsr GI. (B) Southern blot analysis of ES cells by using the 3′ probe. The 67.1-kb EcoRV fragment represents the wild-type allele, whereas the 6.9-kb EcoRV fragment represents the targeted allele. (C) Northern blot analysis of PINK1 transcripts. The blot is hybridized with a probe specific for exon 8, followed by hybridization of a probe specific for GAPDH cDNA as control. (D) Normal morphology of dopaminergic neurons in PINK1−/− mice is indicated by similar TH immunoreactivity in the SNpc of PINK1−/− mice and wilt-type controls at the age of 2–3 months. (E) Similar numbers of TH-positive neurons are present in the SNpc of PINK1−/− and wild-type mice at the ages of 2–3 months (+/+: 13,660 ± 1,033; −/−: 12,520 ± 573; n = 4 per genotype; P > 0.05) and 8–9 months (+/+: 13,547 ± 1,638; −/−: 14,446 ± 1,150; n = 6–7; P > 0.05). (F) Similar striatal content of DA in PINK1−/− mice and wild-type controls at the ages of 2–3 months (+/+: 14.3 ± 0.7; −/−: 13.2 ± 1.8; n = 5 per genotype; P > 0.05) and 8–9 months (+/+: 15.8 ± 0.9, −/−: 17.7 ± 2.3; n = 5–7 per genotype; P > 0.05).
Fig. 2.
Fig. 2.
Evoked release of catecholamine is decreased in PINK1−/− mice. (A) Reduction of evoked DA release in the PINK1−/− striatum. Representative amperometric traces of electrical stimulation-evoked DA release in the absence (control) and the presence of nomifensine are shown on the left. Arrows indicate the onset of electrical pulses. PINK1+/+ slices show a mean evoked DA signal of 26.0 ± 2.3 × 106 molecules, whereas PINK1−/− slices show a lower evoked DA signal of 18.5 ± 2.7 × 106 molecules (*, P < 0.05), indicating a reduction in evoked DA overflow in PINK1−/− mice. In the presence of nomifensine, the mean evoked DA signal in PINK1+/+ striatal slices but not in PINK1−/− striatal slices is significantly increased (60.4 ± 6.4 × 106 molecules) compared with the control condition without nomifensine (26.0 ± 2.3 × 106 molecules; **, P < 0.01). Data in all panels are expressed as mean ± SEM. (B) Reduction of evoked catecholamine release in PINK1−/− chromaffin cells. Amperometric traces of 80 mM K+-evoked catecholamine release are shown at the top. Arrows mark the onset of high K+ stimulation. Total catecholamine release per cell during the 6-second stimulation is much lower in PINK1−/− mice (25.0 ± 2.5 × 106) compared with wild-type controls (50.2 ± 5.0 × 106; **, P < 0.01). The mean catecholamine quantal size is also reduced in PINK1−/− chromaffin cells (52.4 ± 2.6 × 104 compared with PINK1+/+ cells (77.6 ± 3.9 × 104; **, P < 0.01). Frequency of quantal release is significantly lower in PINK1−/− cells, as indicated by a lower mean interspike interval in PINK1+/+ (1.3 ± 0.1) than in PINK1−/− cells (2.1 ± 0.3; **, P < 0.01). Data in all panels are expressed as mean ± SEM.
Fig. 3.
Fig. 3.
Reversal of synaptic plasticity impairment by DA receptor agonists or agents increasing DA release in PINK1−/− mice. (A) Corticostriatal LTP induced by HFS in the absence of Mg2+ in PINK1−/− MS neurons is lower than in controls. Preincubation with the D1 receptor agonist SKF 38393 restores LTP to the level obtained in controls. (B) Corticostriatal LTD induced by HFS in the presence of Mg2+ is absent in PINK1−/− MS neurons. (C) Coadministration of D1 (SKF38393) and D2 receptor (quinpirole) agonists fully restores LTD in PINK1−/− neurons, whereas application of SKF38393 or quinpirole alone partially rescues LTD impairment. (D) Preincubation with nomifensine does not rescue LTD deficits, whereas pretreatment with amphetamine rescues the LTD impairment completely. l-dopa is able to restore, to a significant extent, the striatal LTD deficit. Each data point represents the mean ± SEM of at least four independent observations. In each panel, the superimposed traces representing the EPSPs recorded before (pre) and 20 min after (post) tetanic stimulation are shown above.
Fig. 4.
Fig. 4.
A schematic model for PINK1 function at the nigrostriatal and corticostriatal heterosynapse. This schematic model illustrates the neuromodulatory role of the nigrostriatal input at glutamatergic corticostriatal synapses of striatal medium spiny neurons (MSN). Coincident activation of convergent nigrostriatal dopaminergic and corticostriatal glutamergic inputs elicits synaptic release of DA and glutamate and activation of postsynaptic D1/D2 and NMDA/AMPA receptors, respectively. Activation of D1 receptors is necessary for the induction of LTP at corticostriatal synapses, whereas activation of both D1 and D2 receptors is necessary for induction of LTD. In the absence of PINK1, impaired release of DA from nigrostriatal terminals leads to reduced activation of postsynaptic D1 and D2 receptors, and consequent defects in both LTP and LTD.
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Comment in

  • Physiology versus pathology in Parkinson's disease.
    Nakamura K, Edwards RH. Nakamura K, et al. Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):11867-8. doi: 10.1073/pnas.0704254104. Epub 2007 Jul 10. Proc Natl Acad Sci U S A. 2007. PMID: 17623781 Free PMC article. No abstract available.

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