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. 2012 Dec 12;32(50):18047-53.
doi: 10.1523/JNEUROSCI.2474-12.2012.

Subthalamic Lesion or Levodopa Treatment Rescues Giant GABAergic Currents of PINK1-deficient Striatum

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Free PMC article

Subthalamic Lesion or Levodopa Treatment Rescues Giant GABAergic Currents of PINK1-deficient Striatum

Nathalie Dehorter et al. J Neurosci. .
Free PMC article

Abstract

Cellular electrophysiological signatures of Parkinson's disease described in the pharmacological 6-hydroxydopamine (6-OHDA) animal models of Parkinson's disease include spontaneous repetitive giant GABAergic currents in a subpopulation of striatal medium spiny neurons (MSNs), and spontaneous rhythmic bursts of spikes generated by subthalamic nucleus (STN) neurons. We investigated whether similar signatures are present in Pink1(-/-) mice, a genetic rodent model of the PARK6 variant of Parkinson's disease. Although 9- to 24-month-old Pink1(-/-) mice show reduced striatal dopamine content and release, and impaired spontaneous locomotion, the relevance of this model to Parkinson's disease has been questioned because mesencephalic dopaminergic neurons do not degenerate during the mouse lifespan. We show that 75% of the MSNs of 5- to 7-month-old Pink1(-/-) mice exhibit giant GABAergic currents, occurring either singly or in bursts (at 40 Hz), rather than the low-frequency (2 Hz), low-amplitude, tonic GABAergic drive common to wild-type MSNs of the same age. STN neurons from 5- to 7-month-old Pink1(-/-) mice spontaneously generated bursts of spikes instead of the control tonic drive. Chronic kainic acid lesion of the STN or chronic levodopa treatment reliably suppressed the giant GABAergic currents of MSNs after 1 month and replaced them with the control tonic activity. The similarity between the in vitro resting states of Pink1 MSNs and those of fully dopamine (DA)-depleted MSNs of 6-OHDA-treated mice, together with the beneficial effect of levodopa treatment, strongly suggest that dysfunction of mesencephalic dopaminergic neurons in Pink1(-/-) mice is more severe than expected. The beneficial effect of the STN lesion also suggests that pathological STN activity strongly influences striatal networks in Pink1(-/-) mice.

Figures

Figure 1.
Figure 1.
Spontaneous GABAA currents recorded from MSNs in basal ganglia slices from 5- to 7-month-old wt or Pink1−/− mice. Voltage-clamp recordings of GABAA sPSCs (VH = +10 mV) at two different time scales. A, Tonic pattern of GABAA sPSCs in wt striatum in the absence (70% of MSNs; A1) or rare presence of single sPSCs >200 pA (●) (30% of MSNs; A2). B1, B2, Oscillatory pattern of GABAA sPSCs recorded in Pink1−/− striatum observed in 74% of MSNs and characterized by the frequent presence of giant events: single sPSCs (●) and bursts of sPSCs (■) (B1, B2). B3, Tonic pattern in the remaining MSNs (26%). The calibration of event amplitude is the same for all recordings in A and B and the scale is identical for the left and right column. C (from left to right), Quantification of the data from wt MSNs as shown in A1+A2 (white) and from Pink1−/− MSNs as shown in B1+B2 (black) or B3 (gray). The mean current charge of GABAA sPSCs increased fivefold between A1+A2 and B1+B2. Giant events represented 9% and 38% of the total current charge in A2 and B1+B2, respectively, and the baseline events (<200 pA) represented 91% and 62% of the total current charge in A1+A2 and B1+B2, respectively. The distribution of single giant sPSCs >200 pA shows the increased number of these events and the presence of very large amplitude events (>1000 pA) in B1+B2 compared with A2. Error bars indicate SEM. **p < 0.01.
Figure 2.
Figure 2.
Characteristics of the STN and STN neurons from wt, Pink1−/− and Pink1−/− STN-lesioned mice. Example traces of the spontaneous bursting activity of Pink1−/− STN neurons (current clamp, whole cell, Vm = −70 mV, A, left) compared with the spontaneous tonic activity of wt STN neurons (Vm = −70 mV, B, left) and corresponding inter spike interval histograms (bin: 10 ms) (A, B, middle). Confocal images of the NeuN-positive neurons in Pink1−/− STN from the nonlesioned (A, right) and lesioned (C) sides (stacks of 16 μm thickness). The lesion was restricted to the STN region (STN + part of zona incerta) and did not extend to the thalamus.
Figure 3.
Figure 3.
Spontaneous GABAA currents recorded from MSNs in basal ganglia slices from 5- to 7-month-old Pink1−/− mice bearing a chronic lesion of the STN or chronically treated with levodopa. A, Top, Neurolucida reconstruction of biocytin-filled Pink1−/− MSNs in the absence (left) or presence (right) of an STN lesion. The histogram in the middle indicates the convex hull volume occupied by the corresponding dendritic trees. A, Bottom, 3D Sholl analysis of the dendritic tree of Pink1−/− MSNs in the absence or presence of an STN lesion. B1, B2, Voltage-clamp recordings of GABAA sPSCs (VH = +10 mV, two different time scales) from Pink1−/− MSNs 1 month after STN lesion, showing a tonic pattern (79% of the MSNs; B1) and a tonic pattern with rare giant GABAA sPSCs (21% of MSNs; B2). B3 (from left to right), Quantification of the data from Pink1−/− MSNs from mice bearing a lesion of the STN and comparison with wt or Pink1−/− MSNs. Giant events represented 5% of the total current charge in Pink1−/− MSNs after a lesion of the STN, a value similar to that recorded in wt MSNs (9%), which was sixfold less than in Pink1−/− MSNs (30%). The baseline events (<200 pA) represented 91% and 95% of the total current charge in wt and Pink1−/− MSNs after STN lesion, respectively, but only 62% in Pink1−/− MSNs. The distribution of single giant sPSCs >200 pA shows the decreased number of these events in Pink1−/− MSNs after STN lesion compared with Pink1−/− MSNs in the cells displaying giant sPSCs. C1, C2, Two representative examples of voltage-clamp recordings of GABAA sPSCs (VH = +10 mV, two different time scales) from Pink1−/− MSNs after chronic levodopa treatment, showing a tonic pattern in 100% of the MSNs. C3 (from left to right), Quantification of the data from Pink1−/− MSNs from mice treated with levodopa and comparison with wt or Pink1−/− MSNs: mean current charge of the tonic patterns, percentage of the mean current charge occupied by the giants (0% after levodopa treatment), percentage of the mean current charge occupied by the baseline events (basal), amplitude and frequency of the tonic events. Error bars indicate SEM. *p < 0.05, **p < 0.01, ***p < 0.001. ns, Not significant.

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