Developmental Profile of the Aberrant Dopamine D2 Receptor Response in Striatal Cholinergic Interneurons in DYT1 Dystonia

Sciamanna, Giuseppe; Tassone, Annalisa; Martella, Giuseppina; Mandolesi, Georgia; Puglisi, Francesca; Cuomo, Dario; Madeo, Graziella; Ponterio, Giulia; Standaert, David G.; Bonsi, Paola; Pisani, Antonio

doi:10.1371/journal.pone.0024261

Cited by 80 publications

(76 citation statements)

References 57 publications

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“…Cholinergic interneurons (ChIs) were recorded from parahorizontal brain slices, in which axonal projections arising both from cortex and intralaminar thalamic nuclei are preserved, allowing selective activation of the two distinct pathways (Figure 1A) (Ding et al, 2008; Smeal et al, 2007). In such experimental conditions, ChIs exhibit a tonic firing activity, which did not differ among the different strains of mice (NT: 2.3 ±0.7 Hz, n=40; hWT: 2.0±0.7 Hz, n=33; hMT1: 2.4±0.8 Hz, n=36; p>0.05) (Sciamanna et al, 2011). Synaptic stimulation from either cortex or thalamus induced an excitatory synaptic current (EPSC), comparable among genotypes (Figure 1A1).…”

Section: Resultsmentioning

confidence: 99%

Cholinergic Dysfunction Alters Synaptic Integration between Thalamostriatal and Corticostriatal Inputs in DYT1 Dystonia

et al. 2012

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Projections from thalamic intralaminar nuclei convey sensory signals to striatal cholinergic interneurons. These neurons respond with a pause in their pacemaking activity, enabling synaptic integration with cortical inputs to medium spiny neurons (MSNs), thus playing a crucial role in motor function. In mice with the DYT1 dystonia mutation, stimulation of thalamostriatal axons, mimicking a response to salient events, evoked a shortened pause and triggered an abnormal spiking activity in interneurons. This altered pattern caused a significant rearrangement of the temporal sequence of synaptic activity mediated by M1 and M2 muscarinic receptors in MSNs, consisting of an increase in postsynaptic currents and a decrease of presynaptic inhibition, respectively. Consistent with a major role of acetylcholine, either lowering cholinergic tone or antagonizing postsynaptic M1 muscarinic receptors normalized synaptic activity. Our data demonstrate an abnormal time-window for synaptic integration between thalamostriatal and corticostriatal inputs which might alter the action selection process, thereby predisposing DYT1 gene mutation carriers to develop dystonic movements.

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Section: Resultsmentioning

confidence: 99%

Cholinergic Dysfunction Alters Synaptic Integration between Thalamostriatal and Corticostriatal Inputs in DYT1 Dystonia

et al. 2012

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“…In point of fact, the abnormal cholinergic functioning may result as a secondary effect of the altered dopaminergic neurotransmission in the striatum (34) and this imbalance may have a role in symptom generation, as showed recently in DYT1 animal models (45). …”

Section: Primary Dystoniamentioning

confidence: 97%

PET Neuroimaging: Insights on Dystonia and Tourette Syndrome and Potential Applications

2014

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Primary dystonia (pD) is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Gilles de la Tourette syndrome (GTS) is a childhood-onset neuropsychiatric developmental disorder characterized by motor and phonic tics, which could progress to behavioral changes. GTS and obsessive–compulsive disorders are often seen in comorbidity, also suggesting that a possible overlap in the pathophysiological bases of these two conditions. PET techniques are of considerable value in detecting functional and molecular abnormalities in vivo, according to the adopted radioligands. For example, PET is the unique technique that allows in vivo investigation of neurotransmitter systems, providing evidence of changes in GTS or pD. For example, presynaptic and post-synaptic dopaminergic studies with PET have shown alterations compatible with dysfunction or loss of D2-receptors bearing neurons, increased synaptic dopamine levels, or both. Measures of cerebral glucose metabolism with 18F-fluorodeoxyglucose PET (18F-FDG PET) are very sensitive in showing brain functional alterations as well. 18F-FDG PET data have shown metabolic changes within the cortico-striato-pallido-thalamo-cortical and cerebello-thalamo-cortical networks, revealing possible involvement of brain circuits not limited to basal ganglia in pD and GTS. The aim of this work is to overview PET consistent neuroimaging literature on pD and GTS that has provided functional and molecular knowledge of the underlying neural dysfunction. Furthermore, we suggest potential applications of these techniques in monitoring treatments.

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“…In transgenic mice, the membrane depolarization coupled to the increase in firing discharge induced by quinpirole was coupled to a reduction in the mAHP amplitude, thereby reducing the threshold for action potential discharge. Accordingly, chelation of intracellular calcium completely abolished the effect of quinpirole, suggesting that activation of calcium-dependent potassium conductances plays a role in the altered D2 receptor-mediated response (Sciamanna et al, 2011). …”

Section: Cholinergic Function In Animal Models Of Dystoniamentioning

confidence: 99%

Striatal cholinergic dysfunction as a unifying theme in the pathophysiology of dystonia

Jaunarajs

Bonsi

Chesselet

et al. 2015

Progress in Neurobiology

149

119

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Dystonia is a movement disorder of both genetic and non-genetic causes, which typically results in twisted posturing due to abnormal muscle contraction. Evidence from dystonia patients and animal models of dystonia indicate a crucial role for the striatal cholinergic system in the pathophysiology of dystonia. In this review, we focus on striatal circuitry and the centrality of the acetylcholine system in the function of the basal ganglia in the control of voluntary movement and ultimately clinical manifestion of movement disorders. We consider the impact of cholinergic interneurons (ChIs) on dopamine-acetylcholine interactions and examine new evidence for impairment of ChIs in dysfunction of the motor systems producing dystonic movements, particularly in animal models. We have observed paradoxical excitation of ChIs in the presence of dopamine D2 receptor agonists and impairment of striatal synaptic plasticity in a mouse model of DYT1 dystonia, which are improved by administration of recently developed M1 receptor antagonists. These findings have been confirmed across multiple animal models of DYT1 dystonia and may represent a common endophenotype by which to investigate dystonia induced by other types of genetic and non-genetic causes and to investigate the potential effectiveness of pharmacotherapeutics and other strategies to improve dystonia.

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Developmental Profile of the Aberrant Dopamine D2 Receptor Response in Striatal Cholinergic Interneurons in DYT1 Dystonia

Cited by 80 publications

References 57 publications

Cholinergic Dysfunction Alters Synaptic Integration between Thalamostriatal and Corticostriatal Inputs in DYT1 Dystonia

Cholinergic Dysfunction Alters Synaptic Integration between Thalamostriatal and Corticostriatal Inputs in DYT1 Dystonia

PET Neuroimaging: Insights on Dystonia and Tourette Syndrome and Potential Applications

Striatal cholinergic dysfunction as a unifying theme in the pathophysiology of dystonia

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