Reversal of motor-skill transfer impairment by trihexyphenidyl and reduction of dorsolateral striatal cholinergic interneurons in Dyt1 ΔGAG knock-in mice

Yokoi, Fumiaki; Dang, Mai T.; Zhang, Lin; Dexter, Kelly M.; Efimenko, Iakov; Krishnaswamy, Shiv; Villanueva, Matthew; Misztal, Carly; Gerard, Malinda; Lynch, Patrick J.; Li, Yuqing

doi:10.1016/j.ibneur.2021.05.003

Cited by 4 publications

(8 citation statements)

References 57 publications

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“…The mechanism to produce a high cholinergic tone is still not known. It may relate to the irregular firing of ChIs or the partial loss of ChIs in Dyt1 KI mice (26). The irregular and low-frequency firing of striatal ChIs in Dyt1 KI mice seems consistent with the high striatal acetylcholine tone in the previous reports (79).…”

Section: Discussionsupporting

confidence: 85%

“…Dyt1 KI mice exhibit corticostriatal LTD deficits, abnormal muscle contraction, motor deficits, and impaired motor-skill transfer (8,12,23,25,100). These deficits are ameliorated by THP treatment (23,24,26), suggesting functional alteration of cholinergic or its related circuits in Dyt1 KI mice. As discussed above, the decreased frequency of the ChIs may be caused indirectly by decreased D2R on iMSNs.…”

Section: Discussionmentioning

confidence: 99%

“…No Significant Effect of Trihexyphenidyl on the Firing of the Striatal ChIs in WT and Dyt1 KI Mice THP, a muscarinic acetylcholine receptor M1 antagonist, is effective in treating DYT1 patients and can reverse motor, electrophysiological, and EMG deficits in KI mice (23,24,26). The effect of THP on the spontaneous firing of striatal ChIs was examined to explore whether THP reverses the deficits by acting on striatal ChIs.…”

Section: Equivalent Inhibitory Effect Of Muscarine On the Firing Of T...mentioning

confidence: 99%

“…Dyt1 KI mice exhibit the corticostriatal long-term depression (LTD) deficits (23), sustained contraction and cocontraction of agonist and antagonist muscles of hind limbs (24), motor deficits in the beam-walking test (8), and impaired motorskill transfer (25). These phenotypes are ameliorated by trihexyphenidyl (THP) (23,24,26), suggesting that these phenotypes are caused by the same mechanism as DYT1 dystonia patients.…”

Section: Introductionmentioning

confidence: 99%

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Electrophysiological Characterization of the Striatal Cholinergic Interneurons in Dyt1 ΔGAG Knock-In Mice

Xiao¹,

Yokoi²,

Walker³

et al. 2022

Dystonia

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DYT1 dystonia is an inherited early-onset movement disorder characterized by sustained muscle contractions causing twisting, repetitive movements, and abnormal postures. Most DYT1 patients have a heterozygous trinucleotide GAG deletion mutation (ΔGAG) in DYT1/TOR1A, coding for torsinA. Dyt1 heterozygous ΔGAG knock-in (KI) mice show motor deficits and reduced striatal dopamine receptor 2 (D2R). Striatal cholinergic interneurons (ChIs) are essential in regulating striatal motor circuits. Multiple dystonia rodent models, including KI mice, show altered ChI firing and modulation. However, due to the errors in assigning KI mice, it is essential to replicate these findings in genetically confirmed KI mice. Here, we found irregular and decreased spontaneous firing frequency in the acute brain slices from Dyt1 KI mice. Quinpirole, a D2R agonist, showed less inhibitory effect on the spontaneous ChI firing in Dyt1 KI mice, suggesting decreased D2R function on the striatal ChIs. On the other hand, a muscarinic receptor agonist, muscarine, inhibited the ChI firing in both wild-type (WT) and Dyt1 KI mice. Trihexyphenidyl, a muscarinic acetylcholine receptor M1 antagonist, had no significant effect on the firing. Moreover, the resting membrane property and functions of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, μ-opioid receptors, and large-conductance calcium-activated potassium (BK) channels were unaffected in Dyt1 KI mice. The results suggest that the irregular and low-frequency firing and decreased D2R function are the main alterations of striatal ChIs in Dyt1 KI mice. These results appear consistent with the reduced dopamine release and high striatal acetylcholine tone in the previous reports.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Equivalent Inhibitory Effect Of Muscarine On the Firing Of T...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Electrophysiological Characterization of the Striatal Cholinergic Interneurons in Dyt1 ΔGAG Knock-In Mice

Xiao¹,

Yokoi²,

Walker³

et al. 2022

Dystonia

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“…The goat anti-CTb antibody has been used extensively to detect the beta subunit of cholera toxin (Hegarty et al, 2010(Hegarty et al, , 2018 and preadsorption of this antibody with CTb abolished immunolabeling in rat and rabbit spinal cord sections (Llewellyn-Smith et al, 1995). The VAchT antibody has been used extensively in recent rodent studies to identify cholinergic neurons using immunocytochemistry (Avila et al, 2020;Webber et al,) and VAchT protein levels using Western blotting (Li et al, 2021;Yokoi et al, 2021).…”

Section: Immunocytochemistrymentioning

confidence: 99%

Distinct morphology of cardiac‐ and brown adipose tissue‐projecting neurons in the stellate ganglia of mice

Barrett

Hegarty

Habecker

et al. 2022

Physiological Reports

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Sympathetic neurons that innervate the heart are located primarily in the stellate ganglia (SG), which also contains neurons that project to brown adipose tissue (BAT). These studies were designed to examine the morphology of these two populations (cardiac-and BAT-projecting) and their target connectivity. We examined SG neurons in C57BL/6J mice following injections of the retrograde tracer cholera toxin B (CTb) conjugated to Alexa Fluor 488 and Alexa Fluor 555, into cardiac tissue and intrascapular BAT. BAT-projecting SG neurons were widely dispersed in SG, while cardiac-projecting SG neurons were localized primarily near the inferior cardiac nerve base. SG neurons were not dual-labeled, suggesting that sympathetic innervation is specific to the heart and BAT, supporting the idea of "labeled lines" of efferents. Morphologically, cardiac-projecting SG somata had more volume and were less abundant than BAT-projecting neurons using our tracer-labeling paradigm. We found a positive correlation between the number of primary dendrites per neuron and soma volume in cardiac-projecting SG neurons, though not in BAT-projecting neurons. In both SG subpopulations, the number of cholinergic inputs marked with vesicular acetylcholine transporter (VAChT) puncta contacting the soma was positively correlated to soma volume, suggesting scaling of inputs across a range of neuronal sizes. In separate studies using dual tracing from left and right BAT, we found that BAT-projecting SG neurons were located predominately ipsilateral to the injection, but a small subset of SG neurons project bilaterally to BAT. This tracing approach will allow the assessment of cell-specific mechanisms of plasticity within subpopulations of SG neurons.

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In vivo optogenetic inhibition of striatal parvalbumin‐reactive interneurons induced genotype‐specific changes in neuronal activity without dystonic signs in male DYT1 knock‐in mice

Schulz

Richter

2022

J of Neuroscience Research

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The pathophysiology of early‐onset torsion dystonia (TOR1A/DYT1) remains unclear. Like 70% of human mutation carriers, rodent models with ΔGAG mutation such as DYT1 knock‐in (KI) mice do not show overt dystonia but have subtle sensorimotor deficits and pattern of abnormal synaptic plasticity within the striatal microcircuits. There is evidence that dysfunction of striatal parvalbumin‐reactive (Parv+) fast‐spiking interneurons (FSIs) can be involved in dystonic signs. To elucidate the relevance of these GABAergic interneurons in the pathophysiology of DYT1 dystonia, we used in vivo optogenetics to specifically inhibit Parv+ and to detect changes in motor behavior and neuronal activity. Optogenetic fibers were bilaterally implanted into the dorsal striatum of male DYT1 KI mice and wild‐type (WT) littermates expressing halorhodopsin (eNpHR3.0) in Parv+ interneurons. While stimulations with yellow light pulses for up to 60 min at different pulse durations and interval lengths did not induce abnormal movements, such as dystonic signs, immunohistochemical examinations revealed genotype‐dependent differences. In contrast to WT mice, stimulated DYT1 KI showed decreased striatal neuronal activity, that is, less c‐Fos reactive neurons, and increased activation of cholinergic interneurons after optogenetic inhibition of Parv+ interneurons. These findings suggest an involvement of Parv+ interneurons in an impaired striatal network in DYT1 KI mice, but at least short‐term inhibition of these GABAergic interneurons is not sufficient to trigger a dystonic phenotype, similar to previously shown optogenetic activation of cholinergic interneurons.

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Reversal of motor-skill transfer impairment by trihexyphenidyl and reduction of dorsolateral striatal cholinergic interneurons in Dyt1 ΔGAG knock-in mice

Cited by 4 publications

References 57 publications

Electrophysiological Characterization of the Striatal Cholinergic Interneurons in Dyt1 ΔGAG Knock-In Mice

Electrophysiological Characterization of the Striatal Cholinergic Interneurons in Dyt1 ΔGAG Knock-In Mice

Distinct morphology of cardiac‐ and brown adipose tissue‐projecting neurons in the stellate ganglia of mice

In vivo optogenetic inhibition of striatal parvalbumin‐reactive interneurons induced genotype‐specific changes in neuronal activity without dystonic signs in male DYT1 knock‐in mice

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