Dopamine D2 receptor dysfunction is rescued by adenosine A2A receptor antagonism in a model of DYT1 dystonia

CEINGE Biotecnologie Avanzate, Naples, Italy.
Neurobiology of Disease (Impact Factor: 5.2). 03/2010; 38(3):434-45. DOI: 10.1016/j.nbd.2010.03.003
Source: PubMed

ABSTRACT DYT1 dystonia is an inherited disease linked to mutation in the TOR1A gene encoding for the protein torsinA. Although the mechanism by which this genetic alteration leads to dystonia is unclear, multiple lines of clinical evidence suggest a link between dystonia and a reduced dopamine D2 receptor (D2R) availability. Based on this evidence, herein we carried out a comprehensive analysis of electrophysiological, behavioral and signaling correlates of D2R transmission in transgenic mice with the DYT1 dystonia mutation. Electrophysiological recordings from nigral dopaminergic neurons showed a normal responsiveness to D2-autoreceptor function. Conversely, postsynaptic D2R function in hMT mice was impaired, as suggested by the inability of a D2R agonist to re-establish normal corticostriatal synaptic plasticity and supported by the reduced sensitivity to haloperidol-induced catalepsy. Although an in situ hybridization analysis showed normal D1R and D2R mRNA expression levels in the striata of hMT mice, we found a significant decrease of D2R protein, coupled to a reduced ability of D2Rs to activate their cognate Go/i proteins. Of relevance, we found that pharmacological blockade of adenosine A2A receptors (A2ARs) fully restored the impairment of synaptic plasticity observed in hMT mice. Together, our findings demonstrate an important link between torsinA mutation and D2R dysfunction and suggest that A2AR antagonism is able to counteract the deficit in D2R-mediated transmission observed in mutant mice, opening new perspectives for the treatment of this movement disorder.

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Available from: Alessandro Usiello, Jun 01, 2015
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    • "Thus, the impairment of both LTD and SD demonstrate that a loss of inhibition represents a common trait feature of both mouse and rat models of DYT1 dystonia. Notably, these findings are entirely consistent with previous evidence obtained both in transgenic mice and rats (Grundmann et al., 2012; Martella et al., 2009; Napolitano et al., 2010). Here, we found that the enhancement of LTP may be ascribed, at least partly, to striatal D2R dysfunction. "
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    ABSTRACT: DYT1 dystonia is a movement disorder caused by a deletion in the C-terminal of the protein torsinA. It is unclear how torsinA mutation might disrupt cellular processes encoding motor activity, and whether this impairment occurs in specific brain regions. Here, we report a selective impairment of corticostriatal synaptic plasticity in knock-in mice heterozygous for Δ-torsinA (Tor1a+/Δgag mice) as compared to controls (Tor1a+/+ mice). In striatal spiny neurons from Tor1a+/Δgag mice, high-frequency stimulation failed to induce long-term depression (LTD), whereas long-term potentiation (LTP) exhibited increased amplitude. Of interest, blockade of D2 dopamine receptors (D2Rs) increased LTP in Tor1a+/+ mice to a level comparable to that measured in Tor1a+/Δgag mice and normalized the levels of potentiation across mouse groups. A low-frequency stimulation (LFS) protocol was unable to depotentiate corticostriatal synapses in Tor1a+/Δgag mice. Muscarinic M1 acetylcholine receptor (mAChRs) blockade rescued plasticity deficits. Additionally, we found an abnormal responsiveness of cholinergic interneurons to D2R activation, consisting in an excitatory response rather than the expected inhibition, further confirming an imbalance between dopaminergic and cholinergic signaling in the striatum. Conversely, synaptic activity and plasticity in the CA1 hippocampal region were unaltered in Tor1a+/Δgag mice. Importantly, the M1 mAChR-dependent enhancement of hippocampal LTP was unaffected in both genotypes. Similarly, both basic properties of dopaminergic nigral neurons and their responses to D2R activation were normal. These results provide evidence for a regional specificity of the electrophysiological abnormalities observed and demonstrate the reproducibility of such alterations in distinct models of DYT1 dystonia.
    Neurobiology of Disease 05/2014; 65. DOI:10.1016/j.nbd.2014.01.016 · 5.20 Impact Factor
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    • "How these neurophysiological findings come together to explain dystonia remains conjectural. Nevertheless, one proposed overarching explanation points to dysfunction in internal Globus Pallidus that may in some etiologies be related to abnormal striatal dopaminergic signaling and increased cholinergic tone [56] [57]; this dysfunction leads to abnormal synchronization of the basal ganglia output to the thalamus and sensory feedback misprocessing. Together these mechanisms have the effect of increasing striatal, brainstem, and cortical plasticity and over time producing neural reorganization and overt dystonia. "
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    ABSTRACT: Dystonia has historically been considered a disorder of the basal ganglia. This notion comes from the observation that most lesions responsible for secondary dystonia involve the basal ganglia and from the clinical analogy between primary and secondary dystonia. However, recent evidence coming from neuroimaging, neurophysiological and behavioral studies suggested that the Cerebellum may be involved in the pathophysiology of dystonia. Structural and functional magnetic resonance imaging studies documented a widespread pattern of dysfunction in primary dystonia, thus leading us to reconsider it as a neurodevelopmental motor circuit disorder, characterized by an abnormal functioning of a network of cortical and subcortical areas including the Cerebellum. The most compelling neurophysiological evidence supporting the role of the Cerebellum in the pathophysiology of dystonia comes from studies of the eyeblink conditioning paradigm and of the cerebello-cortical interaction. Preliminary data from patients with primary cervical and focal hand adult-onset dystonia show that performance on the eyeblink conditioning paradigm, which is specifically dependent upon the olivo-cerebellar pathway, is abnormal. Cerebello-cortical interaction can be tested with transcranial magnetic stimulation by investigating how a conditioning stimulus over the Cerebellum influences a subsequent stimulus over the controlateral motor cortex. A reduced cerebellar modulation of motor cortex excitability has been reported in dystonia. At the behavioral level, the dystonia cerebellar function has been explored in a broader range of behaviors. Data present in the literature suggest that the Cerebellum may be involved in the impairment of different abilities in dystonic patients ranging from movement control to sensory perception and motor learning. Overall, this body of evidence suggests that in dystonia the Cerebellum has an abnormal activity; however whether this activity is compensatory, secondary to pathology elsewhere within the sensori-motor network, or plays a primary role in the pathophysiology of dystonia is still open to question.
    12/2012; 2(4):231–235. DOI:10.1016/j.baga.2012.05.003
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    • "Accordingly, we demonstrate that the thalamically-driven pause is a D2R-dependent phenomenon, as sulpiride prevented its generation, suggesting that an altered D2R signaling sustains the abnormal ChIs excitability. These results are consistent with the evidence of a lower expression of striatal D2R protein and reduced ability of D2Rs to activate their cognate Go/i proteins in hMT1 mice (Napolitano et al., 2010). "
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    ABSTRACT: 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 M(1) and M(2) 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 M(1) 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.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 08/2012; 32(35):11991-2004. DOI:10.1523/JNEUROSCI.0041-12.2012 · 6.75 Impact Factor
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