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

PLOS ONE, Sep 2011

Background DYT1 dystonia, a severe form of genetically determined human dystonia, exhibits reduced penetrance among carriers and begins usually during adolescence. The reasons for such age dependence and variability remain unclear. Methods and Results We characterized the alterations in D2 dopamine receptor (D2R) signalling in striatal cholinergic interneurons at different ages in mice overexpressing human mutant torsinA (hMT). An abnormal excitatory response to the D2R agonist quinpirole was recorded at postnatal day 14, consisting of a membrane depolarization coupled to an increase in spiking frequency, and persisted unchanged at 3 and 9 months in hMT mice, compared to mice expressing wild-type human torsinA and non-transgenic mice. This response was blocked by the D2R antagonist sulpiride and depended upon G-proteins, as it was prevented by intrapipette GDP-β-S. Patch-clamp recordings from dissociated interneurons revealed a significant increase in the Cav2.2-mediated current fraction at all ages examined. Consistently, chelation of intracellular calcium abolished the paradoxical response to quinpirole. Finally, no gross morphological changes were observed during development. Conclusions These results suggest that an imbalanced striatal dopaminergic/cholinergic signaling occurs early in DYT1 dystonia and persists along development, representing a susceptibility factor for symptom generation.

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

et al. (2011) Developmental Profile of the Aberrant Dopamine D2 Receptor Response in Striatal Cholinergic Interneurons in DYT1 Dystonia. PLoS ONE 6(9): e24261. doi:10.1371/journal.pone.0024261 Developmental Profile of the Aberrant Dopamine D2 Receptor Response in Striatal Cholinergic Interneurons in DYT1 Dystonia Giuseppe Sciamanna 0 Annalisa Tassone 0 Giuseppina Martella 0 Georgia Mandolesi 0 Francesca Puglisi 0 Dario Cuomo 0 Grazia Madeo 0 Giulia Ponterio 0 David George Standaert 0 Paola Bonsi 0 Antonio Pisani 0 Xiaoxi Zhuang, University of Chicago, United States of America 0 1 Department of Neuroscience, University ''Tor Vergata'' , Rome , Italy , 2 Laboratory of Neurophysiology and Plasticity , Fondazione Santa Lucia I.R.C.C.S., Rome , Italy , 3 Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham , Birmingham, Alabama , United States of America Background: DYT1 dystonia, a severe form of genetically determined human dystonia, exhibits reduced penetrance among carriers and begins usually during adolescence. The reasons for such age dependence and variability remain unclear. Methods and Results: We characterized the alterations in D2 dopamine receptor (D2R) signalling in striatal cholinergic interneurons at different ages in mice overexpressing human mutant torsinA (hMT). An abnormal excitatory response to the D2R agonist quinpirole was recorded at postnatal day 14, consisting of a membrane depolarization coupled to an increase in spiking frequency, and persisted unchanged at 3 and 9 months in hMT mice, compared to mice expressing wild-type human torsinA and non-transgenic mice. This response was blocked by the D2R antagonist sulpiride and depended upon Gproteins, as it was prevented by intrapipette GDP-b-S. Patch-clamp recordings from dissociated interneurons revealed a significant increase in the Cav2.2-mediated current fraction at all ages examined. Consistently, chelation of intracellular calcium abolished the paradoxical response to quinpirole. Finally, no gross morphological changes were observed during development. Conclusions: These results suggest that an imbalanced striatal dopaminergic/cholinergic signaling occurs early in DYT1 dystonia and persists along development, representing a susceptibility factor for symptom generation. - DYT1 dystonia is a common form of inherited, generalized dystonia, with onset in childhood or adolescence, characterized by sustained muscle contractions causing twisting, repetitive movements and progressive abnormal postures [1]. It is produced by a single pathogenic codon deletion in the C-terminal of the protein torsinA, a member of AAA+ (ATPases associated with a variety of cellular activities) protein family of chaperone-like proteins, involved in protein trafficking, membrane fusion and participating in secretory processing [24]. Although at system level the precise consequences of torsinA mutation are still unclear, imbalances in neurotransmission in basal ganglia circuits as well as in the sensorimotor cortex and cerebellum have been documented [57]. Experimental and clinical evidence point to the striatum, where dopamine (DA) and acetylcholine (ACh) interact, as one of the principal sites of network dysfunction in DYT1 dystonia [811]. Although small in number, cholinergic interneurons are the sole source of striatal ACh, playing an essential role both in striatal synaptic plasticity and motor learning, as well as in the pathophysiology of movement disorders, such as Parkinsons disease (PD) and dystonia [1215]. Of note, cholinergic interneurons are exclusively found in regions with a dense dopaminergic innervation, such as the dorsal striatum. In these regions, dopaminergic afferents exert a powerful control over cholinergic transmission. Maintenance of ACh levels is indeed regulated by ACh degrading enzymes, by muscarinic M2/M4 autoreceptors [14,16] but also by an inhibitory DA D2 receptor (D2R) action [1719]. Our previous studies identified a fundamental alteration in the balance between striatal DA and ACh. Normally, activation of D2Rs reduces the activity of cholinergic interneurons, whereas in interneurons from transgenic mice overexpressing human mutant torsinA (hMT), D2R activation dramatically increases, rather than decrease, the spike rate [20]. Because DYT1 dystonia is considered a neurodevelopmental disorder [2,7,9], in the present work we characterized the receptor and post-receptor mechanisms involved in this abnormal response, extending this analysis to different developmental stages. Similarly, the profile of High-Voltage-Activated (HVA) calcium currents was determined in the three strains of mice. Since strong level of torsinA mRNA is observed in cholinergic interneurons from both human and rodent striatum [2123] a morphological analysis of cholinergic interneurons was performed at different ages. Our results demonstrate that torsinA mutation alters striatal function ea (...truncated)


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Giuseppe Sciamanna, Annalisa Tassone, Giuseppina Martella, Georgia Mandolesi, Francesca Puglisi, Dario Cuomo, Grazia Madeo, Giulia Ponterio, David George Standaert, Paola Bonsi, Antonio Pisani. Developmental Profile of the Aberrant Dopamine D2 Receptor Response in Striatal Cholinergic Interneurons in DYT1 Dystonia, PLOS ONE, 2011, 9, DOI: 10.1371/journal.pone.0024261