Vesicular Acetylcholine Transporter Alters Cholinergic Tone and Synaptic Plasticity in DYT1 Dystonia

Annalisa Tassone, Giuseppina Martella, Maria Meringolo, Valentina Vanni, Giuseppe Sciamanna, Giulia Ponterio, Paola Imbriani, Paola Bonsi, Antonio Pisani, Annalisa Tassone, Giuseppina Martella, Maria Meringolo, Valentina Vanni, Giuseppe Sciamanna, Giulia Ponterio, Paola Imbriani, Paola Bonsi, Antonio Pisani

Abstract

Background: Acetylcholine-mediated transmission plays a central role in the impairment of corticostriatal synaptic activity and plasticity in multiple DYT1 mouse models. However, the nature of such alteration remains unclear.

Objective: The aim of the present work was to characterize the mechanistic basis of cholinergic dysfunction in DYT1 dystonia to identify potential targets for pharmacological intervention.

Methods: We utilized electrophysiology recordings, immunohistochemistry, enzymatic activity assays, and Western blotting techniques to analyze in detail the cholinergic machinery in the dorsal striatum of the Tor1a+/- mouse model of DYT1 dystonia.

Results: We found a significant increase in the vesicular acetylcholine transporter (VAChT) protein level, the protein responsible for loading acetylcholine (ACh) from the cytosol into synaptic vesicles, which indicates an altered cholinergic tone. Accordingly, in Tor1a+/- mice we measured a robust elevation in basal ACh content coupled to a compensatory enhancement of acetylcholinesterase (AChE) enzymatic activity. Moreover, pharmacological activation of dopamine D2 receptors, which is expected to reduce ACh levels, caused an abnormal elevation in its content, as compared to controls. Patch-clamp recordings revealed a reduced effect of AChE inhibitors on cholinergic interneuron excitability, whereas muscarinic autoreceptor function was preserved. Finally, we tested the hypothesis that blockade of VAChT could restore corticostriatal long-term synaptic plasticity deficits. Vesamicol, a selective VAChT inhibitor, rescued a normal expression of synaptic plasticity.

Conclusions: Overall, our findings indicate that VAChT is a key player in the alterations of striatal plasticity and a novel target to normalize cholinergic dysfunction observed in DYT1 dystonia. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: acetylcholine; acetylcholinesterase; cholinergic interneurons; striatum; vesicular acetylcholine transporter.

© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Figures

FIG. 1
FIG. 1
VAChT (vesicular acetylcholine transporter) protein level is increased in the striatum of Tor1a+/− mice. (A) Representative confocal fluorescence images of a corticostriatal coronal section confirming cell‐specific expression of VAChT (red) in ChAT (choline acetyltransferase)‐positive cells (cyan) (scale 5×, scale bar 200 μm). Note the absence of immunolabeling in the cortical area. (B) Higher‐magnification images showing cholinergic interneurons located in the dorsal striatum (scale 20×, scale bar 50 μm). (C) Merged image of the two split channels (ChAT‐cyan and VAChT‐red) and the overlapping mask VAChT/ChAT (mk‐white) to better visualize immunoreactivity of VAChT on ChAT‐positive ChIs (cholinergic interneurons) (scale 63xz1.5, scale bar 10 μm). (D–H) Representative Western blots (25 μg of total striatal extract) and the respective densitometry analysis. Histograms show the amount of protein relative to β‐actin (42 kD), used as an internal loading control, and normalized to the wild‐type samples of the same experiment. (D) TorsinA (37 kDa) protein level was reduced in the dorsal striatum of Tor1a+/− mice (Tor1a+/+ 1.20 ± 0.09, N = 8; Tor1a+/− 0.38 ± 0.05, N = 9; unpaired t test P < 0.0001***). (E) CHT1 (~70 kDa), (F) ChAT (~70 kDa), and (G) VGLUT3 (vesicular glutamate transporter 3) (~60 kDa) quantification did not show significant changes in Tor1a+/− striatum (CHT1, Tor1a+/+ 1.000 ± 0.163, N = 4; Tor1a+/− 0.868 ± 0.053, N = 4, unpaired t test P = 0.47; ChAT, Tor1a+/+ 0.99 ± 0.06, N = 9; Tor1a+/− 0.97 ± 0.06, N = 10; unpaired t test P = 0.85; VGLUT3, Tor1a+/+ 1.00 ± 0.15, N = 7; Tor1a+/− 1.01 ± 0.10, N = 8; unpaired t test P = 0.93). (H) VAChT (~70 kDa) densitometry analysis revealed a significant increase in protein level in Tor1a+/− mice (Tor1a+/+ 1.00 ± 0.05, N = 6; Tor1a+/− 1.33 ± 0.10, N = 8; unpaired t test P = 0.0176*). Data are presented as mean ± standard error of the mean (SEM). (I) VAChT mRNA copy numbers in Tor1a+/− and Tor1a+/+ striatal samples were determined by quantitative real‐time polymerase chain reaction. The dot‐plot graph shows the relative expression of VAChT mRNA normalized to the expression of the reference gene Hprt1 for each sample. Tor1a+/− values are presented as fold change (2(–ddCt)) with respect to Tor1a+/+ samples. No statistically significant difference was found between genotypes (1.23 ± 0.18 fold change, N = 9, unpaired t test P = 0.23). Data are presented as mean ± SEM. [Color figure can be viewed at wileyonlinelibrary.com]
FIG. 2
FIG. 2
Increased striatal ACh (acetylcholine) content and AChE (acetylcholinesterase) activity in Tor1a+/− mice. VAChT (vesicular acetylcholine transporter) protein expression in vitro after ACh system modulation. (A) The histogram shows an enhanced basal ACh content in mutant mice (Tor1a+/+ 31.88 ± 15.01 pmol/mg protein, N = 6; Tor1a+/−110.1 ± 27.99 pmol/mg protein, N = 5; unpaired t test P = 0.0293*). (B) Quinpirole (10 μM, 4 minutes) dramatically increases striatal ACh content in Tor1a+/−, as compared to control, mice (Tor1a+/+ 32.34 ± 16.24 pmol/mg protein; N = 3; Tor1a+/− 255.8 ± 24 pmol/mg protein in N = 3; unpaired t test P = 0.001**). (C) The plot shows a significant increase in AChE activity in the dorsal striatum of Tor1a+/− mice (Tor1a+/+ 0.54 ± 0.05 U/mg total proteins, N = 10; Tor1a+/− 0.70 ± 0.06 U/mg total proteins, N = 8; unpaired t test P = 0.048*). [Color figure can be viewed at wileyonlinelibrary.com]
FIG. 3
FIG. 3
Reduced potency of AChE (acetylcholinesterase) inhibitors on the spontaneous firing activity of Tor1a+/− ChIs (cholinergic interneurons). (A, B) Representative patch‐clamp recordings of ChIs in aCSF (artificial cerebrospinal fluid) (top) and after bath application of oxotremorine (Oxo 600 nM, 2 minutes, bottom) in both strains. (C) (Left) Summary plot showing a similar decrease in firing rate induced by 600 nM Oxo in both genotypes (Tor1a+/+: 44.15 ± 7.35% of control; n = 11, N = 5; Tor1a+/−: 35.85 ± 10.07% of control; n = 6, N = 3; unpaired t test P = 0.51). (Right) The dose–response curves show similar kinetics of inhibition in both genotypes (IC50: Tor1a+/+ 499 nM, 95% confidence intervals: 3.463e‐007 to 7.212e‐007; Tor1a+/− 386 nM, 2.522e‐007 to 5.932e‐007; F test P = 0.51). (D, E) Representative traces of cell‐attached recordings from ChIs in aCSF (top) and after bath application of 10 nM (middle) and 500 nM (bottom) neostigmine (Neost, 5 minutes). (F) The histograms summarize the effect of 10 nM (left, Tor1a+/+ 35.11 ± 6.71% of control, n = 8, N = 6; Tor1a+/− 66.07 ± 5.69% of control, n = 9, N = 7; unpaired t test P = 0.0034**) and 500 nM of Neost (right, Tor1a+/+ 14.98 ± 4.44% of control; n = 9, N = 6; Tor1a+/− 24.13 ± 6.01% of control; n = 11, N = 8; unpaired t test P = 0.25). (G) The dose–response curves of Neost inhibitory effect on ChI firing activity show a shift to the right in Tor1a+/− compared to wild‐type cells (Tor1a+/+: IC50 0.271 nM, 1.119e‐010 to 6.598e‐010 confidence interval; Tor1a+/−: IC50 27.12 nM, 6.797e‐009 to 1.082e‐007 95% confidence interval; F test P < 0.0001***). (H) Representative traces of IPSCs (inhibitory postsynaptic currents) evoked in ChIs by paired pulse intrastriatal stimulation (50‐ms interval) in the presence of CNQX (10 μM) and D‐AP5 (20 μM), to avoid glutamate signaling contamination, before (left) and after (right) bath application of Neost (10 μM, 15 minutes). (I) The graphs summarize the effect of Neost on the IPSC amplitude (Tor1a+/+: in aCSF 125.8 ± 12 pA, in Neost 92 ± 10 pA, n = 4, paired t test P = 0.0054**; Tor1a+/−: in aCSF 132.8 ± 6 pA, in Neost 47.3 ± 6 pA, n = 4, paired t test P = 0.019**). The extent of IPSC amplitude reduction is significantly higher in Tor1a+/− mice than in Tor1a+/+ mice (Tor1a+/+ 73.11 ± 3.17% of control, n = 4; Tor1a+/− 35.26 ± 3.32% of control, n = 4; unpaired t test P = 0.0002***). Data are presented as mean ± standard error of the mean. [Color figure can be viewed at wileyonlinelibrary.com]
FIG. 4
FIG. 4
Inhibition of VAChT (vesicular acetylcholine transporter) rescues LTD (long‐term depression) in Tor1a+/− mice. (A) Slice perfusion with the VAChT‐blocking agent vesamicol (20 μM, 20 minutes) does not modify the paired‐pulse ratio (PPR) of corticostriatal EPSPs (excitatory postsynaptic potentials) in Tor1a+/+ MSNs, as shown by (left) the representative traces of intracellular recordings and (right) the summary plot (in aCSF [artificial cerebrospinal fluid] 1.06 ± 0.01, n = 5, N = 4; in vesamicol 1.03 ± 0.03, n = 5, N = 4; paired t test P = 0.268). (B) Vesamicol does not modify the PPR of corticostriatal EPSPs in Tor1a+/− MSNs: (left) representative traces of intracellular recordings and (right) summary plot (in aCSF 1.08 ± 0.01, n = 6, N = 4; in vesamicol 1.09 ± 0.03, n = 6, N = 4; paired t test P = 0.682). (C) Time course of corticostriatal LTD induced by HFS (high‐frequency stimulation) (black arrow) in Tor1a+/+ MSN, either in aCSF (black circles) or in 20‐μM vesamicol (red circles). (D) Time course of corticostriatal LTD, induced by HFS (black arrow) in Tor1a+/− MSN, either in aCSF (black circles) or in 20‐μM vesamicol (red circles). (E) The amplitude of Tor1a+/+ corticostriatal LTD was similar in aCSF and in vesamicol (aCSF, black circles: pre‐HFS 25.92 ± 2.04 mV; post‐HFS 16.82 ± 1.76 mV; n = 6, N = 4; paired t test P < 0.0001***; vesamicol, red circles: pre‐HFS: 22.05 ± 2.50; post‐HFS 10.73 ± 1.95 mV; n = 6, N = 5; paired t test P = 0.0002***). (F) HFS did not induce a corticostriatal LTD in Tor1a+/− MSNs (aCSF, black circles: pre‐HFS 20.23 ± 3.48 mV; post‐HFS 21.53 ± 4.04 mV; n = 9, N = 5; paired t test P = 0.4555). Vesamicol preincubation was able to rescue LTD expression in the striatum of Tor1a+/− mice (pre‐HFS 20.25 ± 2.07 mV; post‐HFS 12.74 ± 1.60 mV; n = 7, N = 5; paired t test P = 0.0005***). [Color figure can be viewed at wileyonlinelibrary.com]
FIG. 5
FIG. 5
Simplified model of cholinergic synaptic dysfunction in DYT1 dystonia. (Left) Cartoon showing normal signaling between ChIs (cholinergic interneurons) and MSNs, leading to the expression of normal LTD (long‐term depression). In DYT1 dystonia (right), synaptic vesicles contain more VAChT (vesicular acetylcholine transporter), which allows to store significant amounts of ACh. During LTD induction, activation of an abnormal D2R (dopamine 2 receptor) increases the release of these vesicles fully loaded with ACh into the synaptic cleft. Despite the increase in AChE (acetylcholinesterase) activity, which helps degrading ACh, the excessive cholinergic tone disrupts the expression of synaptic plasticity in MSNs. [Color figure can be viewed at wileyonlinelibrary.com]

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