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: 5.08). 03/2010; 38(3):434-45. DOI: 10.1016/j.nbd.2010.03.003
Source: PubMed


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.
    Full-text · Article · May 2014 · Neurobiology of Disease
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    • "These findings are supported by the accumulating body of data obtained using transgenic mice and rats that overexpress ΔE-torsinA. For example, long-term depression is abolished at cortico-striatal synapses [37,41,53], whereas long-term potentiation is enhanced [37,53] and cannot be reverted to the baseline, non-potentiated level (lack synaptic depotentiation) [37,41,53]. Furthermore, intra-striatal GABAergic transmission is enhanced [38] and dopaminergic transmission is suppressed [54,55]. "
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    ABSTRACT: DYT1 dystonia is the most common hereditary form of primary torsion dystonia. This autosomal-dominant disorder is characterized by involuntary muscle contractions that cause sustained twisting and repetitive movements. It is caused by an in-frame deletion in the TOR1A gene, leading to the deletion of a glutamic acid residue in the torsinA protein. Heterozygous knock-in mice, which reproduce the genetic mutation in human patients, have abnormalities in synaptic transmission at the principal GABAergic neurons in the striatum, a brain structure that is involved in the execution and modulation of motor activity. However, whether this mutation affects the excitability of striatal GABAergic neurons has not been investigated in this animal model. Here, we examined the excitability of cultured striatal neurons obtained from heterozygous knock-in mice, using calcium imaging as indirect readout. Immunofluorescence revealed that more than 97% of these neurons are positive for a marker of GABAergic neurons, and that more than 92% are also positive for a marker of medium spiny neurons, indicating that these are mixed cultures of mostly medium spiny neurons and a few (~5%) GABAergic interneurons. When these neurons were depolarized by field stimulation, the calcium concentration in the dendrites increased rapidly and then decayed slowly. The amplitudes of calcium transients were larger in heterozygous neurons than in wild-type neurons, resulting in ~15% increase in cumulative calcium transients during a train of stimuli. However, there was no change in other parameters of calcium dynamics. Given that calcium dynamics reflect neuronal excitability, these results suggest that the mutation only slightly increases the excitability of striatal GABAergic neurons in DYT1 dystonia.
    Full-text · Article · Nov 2013 · PLoS ONE
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    • "A transgenic mouse model, ectopically overexpressing human torsinAΔE derived by human CMV immediate early promoter, exhibits an imbalance between striatal dopaminergic and cholinergic signaling [35]. The transgenic mice also show a reduction of dopamine receptor 2 in the striatum and impaired LTD, and the LTD was rescued by an adenosine A2A receptor antagonist [36]. However, PPR was normal when measured in the corticostriatal pathway only at 50 msec inter-stimulus interval [35]. "
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    ABSTRACT: DYT1 early-onset generalized torsion dystonia (DYT1 dystonia) is an inherited movement disorder caused by mutations in one allele of DYT1 (TOR1A), coding for torsinA. The most common mutation is a trinucleotide deletion (ΔGAG), which causes a deletion of a glutamic acid residue (ΔE) in the C-terminal region of torsinA. Although recent studies using cultured cells suggest that torsinA contributes to protein processing in the secretory pathway, endocytosis, and the stability of synaptic proteins, the nature of how this mutation affects synaptic transmission remains unclear. We previously reported that theta-burst-induced long-term potentiation (LTP) in the CA1 region of the hippocampal slice is not altered in Dyt1 ΔGAG heterozygous knock-in (KI) mice. Here, we examined short-term synaptic plasticity and synaptic transmission in the hippocampal slices. Field recordings in the hippocampal Schaffer collaterals (SC) pathway revealed significantly enhanced paired pulse ratios (PPRs) in Dyt1 ΔGAG heterozygous KI mice, suggesting an impaired synaptic vesicle release. Whole-cell recordings from the CA1 neurons showed that Dyt1 ΔGAG heterozygous KI mice exhibited normal miniature excitatory post-synaptic currents (mEPSC), suggesting that action-potential independent spontaneous pre-synaptic release was normal. On the other hand, there was a significant decrease in the frequency, but not amplitude or kinetics, of spontaneous excitatory post-synaptic currents (sEPSC) in Dyt1 ΔGAG heterozygous KI mice, suggesting that the action-potential dependent pre-synaptic release was impaired. Moreover, hippocampal torsinA was significantly reduced in Dyt1 ΔGAG heterozygous KI mice. Although the hippocampal slice model may not represent the neurons directly associated with dystonic symptoms, impaired release of neurotransmitters caused by partial dysfunction of torsinA in other brain regions may contribute to the pathophysiology of DYT1 dystonia.
    Preview · Article · Aug 2013 · PLoS ONE
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