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. 2009 Feb;215(2):388-96.
doi: 10.1016/j.expneurol.2008.11.001. Epub 2008 Nov 21.

Enhanced sensitivity to group II mGlu receptor activation at corticostriatal synapses in mice lacking the familial parkinsonism-linked genes PINK1 or Parkin

G Martella  1 , P Platania, D Vita, G Sciamanna, D Cuomo, A Tassone, A Tscherter, T Kitada, P Bonsi, J Shen, A Pisani
Affiliations

Enhanced sensitivity to group II mGlu receptor activation at corticostriatal synapses in mice lacking the familial parkinsonism-linked genes PINK1 or Parkin

G Martella et al. Exp Neurol. 2009 Feb.

Abstract

An altered glutamatergic input at corticostriatal synapses has been shown in experimental models of Parkinson's disease (PD). In the present work, we analyzed the membrane and synaptic responses of striatal neurons to metabotropic glutamate (mGlu) receptor activation in two different mouse models of inherited PD, linked to mutations in PINK1 or Parkin genes. Both in PINK1 and Parkin knockout ((-/-)) mice, activation of group I mGlu receptors by 3,5-DHPG caused a membrane depolarization coupled to an increase in firing frequency in striatal cholinergic interneurons that was comparable to the response observed in the respective wild-type (WT) interneurons. The sensitivity to group II and III mGlu receptors was tested on cortically-evoked excitatory postsynaptic potentials (EPSPs) recorded from medium spiny neurons (MSNs). Both LY379268 and L-AP4, agonists for group II and III, respectively, had no effect on intrinsic membrane properties, but dose-dependently reduced the amplitude of corticostriatal EPSPs. However, both in PINK1(-/-) and Parkin(-/-) mice, LY379268, but not L-AP4, exhibited a greater potency as compared to WT in depressing EPSP amplitude. Accordingly, the dose-response curve for the response to LY379268 in both knockout mice was shifted leftward. Moreover, consistent with a presynaptic site of action, both LY379268 and L-AP4 increased the paired-pulse ratio either in PINK1(-/-) and Parkin(-/-) or in WT mice. Acute pretreatment with L-dopa did not rescue the enhanced sensitivity to LY379268. Together, these results suggest that the selective increase in sensitivity of striatal group II mGlu receptors represents an adaptive change in mice in which an altered dopamine metabolism has been documented.

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Figures

Fig. 1
Fig. 1
Normal intrinsic and synaptic properties in PINK1−/− and Parkin−/− mice. (A) Current-clamp recordings obtained from a WT MSN showing a tonic firing activity induced by a depolarizing current step (800 pA, 700 ms, upper trace). No significant difference is observed when the same protocol is applied to MSN from PINK1−/− (middle trace) or Parkin−/− (lower trace) mice. Similar voltage responses are observed when current steps in the hyperpolarizing direction (−800 pA, 700 ms) were applied in the three strains (downward deflections). (B) Sharp intracellular recordings showing synaptic responses to paired stimulation (50 ms interstimulus interval) in WT (upper trace), PINK1−/− (middle trace) and Parkin−/− mice (lower trace) in control condition and in the presence of baclofen (10 μM) in the perfusing solution. Note the large decrease in EPSP amplitude as well as the increase in paired-pulse ratio (PPR, EPSP2/EPSP1) induced by baclofen (grey trace). No difference is observed in the extent of inhibition in WT and PINK1−/− or Parkin−/− mice. The graph shows that the inhibitory effect of baclofen was associated to an increase in PPR in the different genotypes, as expected for a presynaptic site of action. Each data point represents the mean±SEM of at least four individual experiments. (C) Sample traces of sEPSCs (downward deflections) recorded from MSNs in the presence of bicuculline (10 μM) in PINK1−/− and Parkin−/− and their respective WT littermates. Cells were clamped at −80 mV. The graphs show no significant changes in mean frequency of both sEPSCs and mEPSCs (recorded in the presence of TTX), between WT and knockouts.
Fig. 2
Fig. 2
Normal properties and responses to group I mGlu receptor activation in cholinergic interneurons. (A) Sample traces showing the voltage responses to current steps in a cholinergic interneuron from WT mice. Depolarizing steps (100 pA, 1.5 s) evoke firing discharge with a rapid spike accommodation. Note also the pronounced afterhyperpolarization at the end of the depolarizing pulse. Hyperpolarizing current pulse (−400 pA, 1.5 s) evokes a prominent sag conductance, indicative of an Ih current. No significant difference was observed in PINK1−/− (middle trace) or Parkin−/− (lower trace). (B) In WT mice, bath-application of the group I mGlu agonist 3,5-DHPG (50 μM, 30 s) induced a transient membrane depolarization coupled to action potential discharge (upper trace). Similarly in cholinergic interneurons from both PINK1−/− (middle trace) or Parkin−/− (lower trace), 3,5-DHPG (50 μM, 30 s), caused a depolarizing response of similar amplitude. On drug washout, membrane potential rapidly recovered to control levels. Note that action potentials were truncated.
Fig. 3
Fig. 3
Enhanced sensitivity to group II mGlu receptor activation in PINK1−/− and Parkin−/− ice. (A) Representative traces of glutamate-mediated corticostriatal excitatory postsynaptic potentials (EPSPs) recorded from MSN of WT mice. The superimposed EPSPs show the inhibitory effect of the group II mGlu receptor agonist LY379268 (1 μM, 3 min) as compared to the control EPSP (CTL). (B, C) In PINK1−/− as well as in Parkin−/− mice, the same concentration of LY379268 causes a significantly stronger inhibition of EPSP. (D) The dose–response curve for the inhibitory effects of LY379268 on the EPSP amplitude in the three genotypes expressed as percent of control. Note the leftward shift in the response to LY379268 in both Parkin−/− and PINK1−/− mice. The IC50 was significantly lower in the latter strains as compared to their WT littermates (see Results for details). Each point represents the mean of at least 8 independent observations.
Fig. 4
Fig. 4
Group III mGlu receptor activation in PINK1−/− and Parkin−/− mice. (A) Sample EPSPs recorded from WT mice in controls (CTL) and after bath-application of the group III mGlu receptor agonist L-AP4 (10 μM, 3 min). No significant difference in the efficacy of L-AP4 was observed either in PINK1−/− and in Parkin−/− mice (B, C). (D) The dose-dependent inhibitory action of L-AP4 did not differ among the two mutant mice, compared to WT mice. Each data point is the average of at least 6 individual experiments.
Fig. 5
Fig. 5
LY379268 increases the Paired-Pulse Ratio in PINK1−/− and Parkin−/− mice. (A) Representative traces showing pairs of synaptic stimuli, separated by 50 ms, applied with a repetition rate of 0.1 Hz. LY379268 (1 μM, 3 min) increased the Paired-Pulse Ratio (PPR) in WT mice, as well as in PINK1−/− and Parkin−/− mice (B, C). (D) The plot summarizes the PPR experiments in the three strains, showing the net increase in PPR, measured as the ratio between EPSP2/EPSP1 in control conditions (CTL) or in the presence of the drug.
Fig. 6
Fig. 6
L-AP4 increases the Paired-Pulse Ratio in PINK1−/− and Parkin−/− mice. (A) Superimposed traces showing the efficacy of L-AP4 (10 μM, 3 min) in reducing the EPSP amplitude and increasing the PPR in WT, PINK1−/− and Parkin−/− mice (B, C). (D) Summary of the PPR experiments in the three strains, showing no significant change among the three strains.
Fig. 7
Fig. 7
Effects of dopamine replacement. Sample recordings from either PINK1−/− or Parkin−/− mice obtained from slices pretreated (20–30 min) with 100 μM L-Dopa. Superimposed traces showing the net reduction of EPSP amplitude by LY379268 (1 μM). The plot summarizes the effects of LY379268 in WT, PINK1−/− and Parkin−/− mice in untreated or L-Dopa-treated slices.
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