Altered postnatal maturation of striatal GABAergic interneurons in a phenotypic animal model of dystonia

Bode, Christoph; Richter, Franziska; Spröte, C.; Brigadski, Tanja; Bauer, Anne; Fietz, Simone A.; Fritschy, Jean‐Marc; Richter, Angelika

doi:10.1016/j.expneurol.2016.10.013

Cited by 30 publications

(18 citation statements)

References 64 publications

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“…Among those are the fast spiking PV-positive GABAergic cells, known to play a major role in feedforward inhibition of GABAergic spiny projection neurons (Tepper et al, 2008 ). Although our recent study did not reveal any significant difference in the number of PV-positive GABAergic interneurons in the striatum of DYT-1 mice (Song et al, 2013 ), data from the d tsz hamster model of primary paroxysmal dystonia showed a significant and widespread loss, and maturation delay, of PV-positive striatal neurons (Gernert et al, 2000 ; Bode et al, 2017 ). Reiner et al ( 2013 ) recently suggested that the progressive loss of PV-positive neurons in the motor striatum may determine the timing of dystonia onset in a mouse model of Huntington’ disease.…”

Section: Discussionmentioning

confidence: 74%

Striatal Cholinergic Interneurons in a Knock-in Mouse Model of L-DOPA-Responsive Dystonia

Yalçın‐Çakmaklı

Rose

Villalba

et al. 2018

Front. Syst. Neurosci.

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Striatal cholinergic dysfunction is a common phenotype associated with various forms of dystonia in which anti-cholinergic drugs have some therapeutic benefits. However, the underlying substrate of striatal cholinergic defects in dystonia remain poorly understood. In this study, we used a recently developed knock-in mouse model of dopamine-responsive dystonia (DRD) with strong symptomatic responses to anti-cholinergic drugs, to assess changes in the prevalence and morphology of striatal cholinergic interneurons (ChIs) in a model of generalized dystonia. Unbiased stereological neuronal counts and Sholl analysis were used to address these issues. To determine the potential effect of aging on the number of ChIs, both young (3 months old) and aged (15 months old) mice were used. For purpose of comparisons with ChIs, the number of GABAergic parvalbumin (PV)-immunoreactive striatal interneurons was also quantified in young mice. Overall, no significant change in the prevalence of ChIs and PV-immunoreactive cells was found throughout various functional regions of the striatum in young DRD mice. Similar results were found for ChIs in aged animals. Subtle changes in the extent and complexity of the dendritic tree of ChIs were found in middle and caudal regions of the striatum in DRD mice. Additional immunohistochemical data also suggested lack of significant change in the expression of striatal cholinergic M1 and M4 muscarinic receptors immunoreactivity in DRD mice. Thus, together with our previous data from a knock-in mouse model of DYT-1 dystonia (Song et al., 2013), our data further suggest that the dysregulation of striatal cholinergic transmission in dystonia is not associated with major neuroplastic changes in the morphology or prevalence of striatal ChIs.Highlights There is no significant change in the number of striatal ChIs in young and aged mice model of DRDThere is no significant change in the prevalence of striatal GABAergic PV-containing interneurons in the striatum of young mice models of DRDSubtle morphological changes in the dendritic arborization of striatal ChIs are found in the middle and caudal tiers of the striatum in young mice models of DRDThe levels of both M1 and M4 muscarinic receptors immunoreactivity are not significantly changed in the striatum of DRD miceMajor changes in the prevalence and morphology of striatal ChIs are unlikely to underlie striatal cholinergic dysfunction in DRD

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Section: Discussionmentioning

confidence: 74%

Striatal Cholinergic Interneurons in a Knock-in Mouse Model of L-DOPA-Responsive Dystonia

Yalçın‐Çakmaklı

Rose

Villalba

et al. 2018

Front. Syst. Neurosci.

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“…Patients with isolated dystonia had enhanced somatosensory temporal discrimination threshold and reduced suppression of paired-pulse SEPs ( 8 , 9 ), which were also observed in our patients who all presenting by paroxysmal dystonia. In the hamster model with the phenotype of dystonia, maturation of striatal GABAergic interneuron is delayed ( 53 ). Reduced functional connectivity of somatosensory network is involved in the pathomechanism of writer's cramp as well ( 54 ).…”

Section: Discussionmentioning

confidence: 99%

Aberrant Sensory Gating of the Primary Somatosensory Cortex Contributes to the Motor Circuit Dysfunction in Paroxysmal Kinesigenic Dyskinesia

et al. 2018

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Paroxysmal kinesigenic dyskinesia (PKD) is conventionally regarded as a movement disorder (MD) and characterized by episodic hyperkinesia by sudden movements. However, patients of PKD often have sensory aura and respond excellently to antiepileptic agents. PRRT2 mutations, the most common genetic etiology of PKD, could cause epilepsy syndromes as well. Standing in the twilight zone between MDs and epilepsy, the pathogenesis of PKD is unclear. Gamma oscillations arise from the inhibitory interneurons which are crucial in the thalamocortical circuits. The role of synchronized gamma oscillations in sensory gating is an important mechanism of automatic cortical inhibition. The patterns of gamma oscillations have been used to characterize neurophysiological features of many neurological diseases, including epilepsy and MDs. This study was aimed to investigate the features of gamma synchronizations in PKD. In the paired-pulse electrical-stimulation task, we recorded the magnetoencephalographic data with distributed source modeling and time-frequency analysis in 19 patients of newly-diagnosed PKD without receiving pharmacotherapy and 18 healthy controls. In combination with the magnetic resonance imaging, the source of gamma oscillations was localized in the primary somatosensory cortex. Somatosensory evoked fields of PKD patients had a reduced peak frequency (p < 0.001 for the first and the second response) and a prolonged peak latency (the first response p = 0.02, the second response p = 0.002), indicating the synchronization of gamma oscillation is significantly attenuated. The power ratio between two responses was much higher in the PKD group (p = 0.013), indicating the incompetence of activity suppression. Aberrant gamma synchronizations revealed the defective sensory gating of the somatosensory area contributes the pathogenesis of PKD. Our findings documented disinhibited cortical function is a pathomechanism common to PKD and epilepsy, thus rationalized the clinical overlaps of these two diseases and the therapeutic effect of antiepileptic agents for PKD. There is a greater reduction of the peak gamma frequency in PRRT2-related PKD than the non-PRRT PKD group (p = 0.028 for the first response, p = 0.004 for the second response). Loss-of-function PRRT2 mutations could lead to synaptic dysfunction. The disinhibiton change on neurophysiology reflected the impacts of PRRT2 mutations on human neurophysiology.

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“…However, a sparing of parvalbumin neurons could be desirable not only for HD, but also in other hyperkinetic neurological disorders. Indeed, striatal parvalbumin expression is decreased in a dystonic hamster model (Bode et al, 2017 ). Thus, disorders where parvalbumin interneurons fast spiking activity is involved such as dystonia could benefit from such neuroprotective effect (Reiner et al, 2003 ).…”

Section: Discussionmentioning

confidence: 99%

Selective Sparing of Striatal Interneurons after Poly (ADP-Ribose) Polymerase 1 Inhibition in the R6/2 Mouse Model of Huntington’s Disease

et al. 2017

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Poly (ADP-ribose) polymerases (PARPs) are enzymes that catalyze ADP-ribose units transfer from NAD to their substrate proteins. It has been observed that PARP-1 is able to increase both post-ischemic and excitotoxic neuronal death. In fact, we have previously shown that, INO-1001, a PARP-1 inhibitor, displays a neuroprotective effect in the R6/2 model of Huntington’s disease (HD). In this study, we investigated the effects of PARP-1-inhibition on modulation of phosphorylated c-AMP response element binding protein (pCREB) and CREB-binding protein (CBP) localization in the different striatal neuronal subsets. Moreover, we studied the neurodegeneration of those interneurons that are particularly vulnerable to HD such as parvalbuminergic and calretininergic, and of other subclasses of interneurons that are known to be resistant, such as cholinergic and somatostatinergic interneurons. Transgenic mice were treated with INO-1001 (10 mg/Kg daily) starting from 4 weeks of age. Double-label immunofluorescence was performed to value the distribution of CBP in ubiquitinated Neuronal intranuclear inclusions (NIIs) in the striatum. INO-1001-treated and saline-treated brain sections were incubated with: goat anti-choline acetyl transferase; goat anti-nitric oxide synthase; mouse anti-parvalbumin and mouse anti-calretinin. Morphometric evaluation and cell counts were performed. Our study showed that the PARP inhibitor has a positive effect in sparing parvalbumin and calretinin-containing interneurons of the striatum, where CREB was upregulated. Moreover, INO-1001 promoted CBP localization into the nuclei of the R6/2 mouse. The sum of our data corroborates the previous observations indicating PARP inhibition as a possible therapeutic tool to fight HD.

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Altered postnatal maturation of striatal GABAergic interneurons in a phenotypic animal model of dystonia

Cited by 30 publications

References 64 publications

Striatal Cholinergic Interneurons in a Knock-in Mouse Model of L-DOPA-Responsive Dystonia

Striatal Cholinergic Interneurons in a Knock-in Mouse Model of L-DOPA-Responsive Dystonia

Aberrant Sensory Gating of the Primary Somatosensory Cortex Contributes to the Motor Circuit Dysfunction in Paroxysmal Kinesigenic Dyskinesia

Selective Sparing of Striatal Interneurons after Poly (ADP-Ribose) Polymerase 1 Inhibition in the R6/2 Mouse Model of Huntington’s Disease

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