Impaired Decision Making and Loss of Inhibitory-Control in a Rat Model of Huntington Disease

Cognitive deficits associated with Huntington disease (HD) are generally dominated by executive function disorders often associated with disinhibition and impulsivity/compulsivity. Few studies have directly examined symptoms and consequences of behavioral disinhibition in HD and its relation with decision-making. To assess the different forms of impulsivity in a transgenic model of HD (tgHD rats), two tasks assessing cognitive/choice impulsivity were used: risky decision-making with a rat gambling task (RGT) and intertemporal choices with a delay discounting task (DD). To assess waiting or action impulsivity the differential reinforcement of low rate of responding task (DRL) was used. In parallel, the volume as well as cellular activity of the amygdala was analyzed. In contrast to WT rats, 15 months old tgHD rats exhibited a poor efficiency in the RGT task with difficulties to choose advantageous options, a steep DD curve as delays increased in the DD task and a high rate of premature and bursts responses in the DRL task. tgHD rats also demonstrated a concomitant and correlated presence of both action and cognitive/choice impulsivity in contrast to wild type (WT) animals. Moreover, a reduced volume associated with an increased basal cellular activity of the central nucleus of amygdala indicated a dysfunctional amygdala in tgHD rats, which could underlie inhibitory dyscontrol. In conclusion, tgHD rats are a good model for impulsivity disorder that could be used more widely to identify potential pharmacotherapies to treat these invasive symptoms in HD

Rescue of striatal long-term depression by chronic mGlu5 receptor negative allosteric modulation in distinct dystonia models

An impairment of long-term synaptic plasticity is considered as a peculiar endophenotype of distinct forms of dystonia, a common, disabling movement disorder. Among the few therapeutic options, broad-spectrum antimuscarinic drugs are utilized, aimed at counteracting abnormal striatal acetylcholine-mediated transmission, which plays a crucial role in dystonia pathophysiology. We previously demonstrated a complete loss of long-term synaptic depression (LTD) at corticostriatal synapses in rodent models of two distinct forms of isolated dystonia, resulting from mutations in the TOR1A (DYT1), and GNAL (DYT25) genes. In addition to anticholinergic agents, the aberrant excitability of striatal cholinergic cells can be modulated by group I metabotropic glutamate receptor subtypes (mGlu1 and 5). Here, we tested the efficacy of the negative allosteric modulator (NAM) of metabotropic glutamate 5 (mGlu) receptor, dipraglurant (ADX48621) on striatal LTD. We show that, whereas acute treatment failed to rescue LTD, chronic dipraglurant rescued this form of synaptic plasticity both in DYT1 mice and GNAL rats. Our analysis of the pharmacokinetic profile of dipraglurant revealed a relatively short half-life, which led us to uncover a peculiar time-course of recovery based on the timing from last dipraglurant injection. Indeed, striatal spiny projection neurons (SPNs) recorded within 2 h from last administration showed full expression of synaptic plasticity, whilst the extent of recovery progressively diminished when SPNs were recorded 4–6 h after treatment. Our findings suggest that distinct dystonia genes may share common signaling pathway dysfunction. More importantly, they indicate that dipraglurant might be a potential novel therapeutic agent for this disabling disorder

Impaired dopamine- and adenosine-mediated signaling and plasticity in a novel rodent model for DYT25 dystonia

Dystonia is a neurological movement disorder characterized by sustained or intermittent involuntary muscle contractions. Loss-of-function mutations in the GNAL gene have been identified to be the cause of "isolated" dystonia DYT25. The GNAL gene encodes for the guanine nucleotide-binding protein G(olf) subunit alpha (G alpha(olf)), which is mainly expressed in the olfactory bulb and the striatum and functions as a modulator during neurotransmission coupling with D1R and A2AR. Previously, heterozygous G alpha(olf)-deficient mice (Gnar(+/-)) have been generated and showed a mild phenotype at basal condition. In contrast, homozygous deletion of Gnal in mice (Gnarl(-/-)) resulted in a significantly reduced survival rate. In this study, using the CRISPR-Cas9 system we generated and characterized heterozygous Gnal knockout rats (Gnarl(+/-)) with a 13 base pair deletion in the first exon of the rat Goal splicing variant 2, a major isoform in both human and rat striatum. Gnarl(+/-) rats showed early-onset phenotypes associated with impaired dopamine transmission, including reduction in locomotor activity, deficits in rotarod performance and an abnormal motor skill learning ability. At cellular and molecular level, we found down-regulated Arc expression, increased cell surface distribution of AMPA receptors, and the loss of D2R-dependent corticostriatal long-term depression (LTD) in Gnarl(+/-) rats. Based on the evidence that D2R activity is normally inhibited by adenosine A2ARs, co-localized on the same population of striatal neurons, we show that blockade of A2ARs restores physiological LTD. This animal model may be a valuable tool for investigating G alpha(olf) function and finding a suitable treatment for dystonia associated with deficient dopamine transmission

DYT6 mutated THAP1 is a cell type dependent regulator of the SP1 family

DYT6 dystonia is caused by mutations in the transcription factor THAP1. THAP1 knock-out or knock-in mouse models revealed complex gene expression changes which are potentially responsible for the pathogenesis of DYT6 dystonia. However, how THAP1 mutations lead to these gene expression alterations and whether the gene expression changes are also reflected in the brain of THAP1 patients are still unclear. In this study we used epigenetic and transcriptomic approaches combined with multiple model systems (THAP1 patients' frontal cortex, THAP1 patients' iPSCs derived midbrain dopaminergic neurons, THAP1 heterozygous knock-out rat model, and THAP1 heterozygous knock-out SH-SY5Y cell lines) to uncover a novel function of THAP1 and the potential pathogenesis of DYT6 dystonia. We observed that THAP1 targeted only a minority of differentially expressed genes caused by its mutation. THAP1 mutations lead to dysregulation of genes mainly through regulation of SP1 family members, SP1 and SP4, in a cell type dependent manner. Comparing global differentially expressed genes detected in THAP1 patients' iPSCs derived midbrain dopaminergic neurons and THAP1 heterozygous knock-out rat striatum, we observed many common dysregulated genes and 61 of them are involved in dystonic syndromes related pathways, like synaptic transmission, nervous system development, and locomotor behavior. Further behavioral and electrophysiological studies confirmed the involvement of these pathways in THAP1 knock-out rats. Taking together, our study characterized the function of THAP1 and contributes to the understanding of the pathogenesis of primary dystonia in human and rat. As SP1 family members are dysregulated in some neurodegenerative diseases, our data may link THAP1 dystonia to multiple neurological diseases and may thus provide common treatment targets

Lung Cancer Among Firefighters: Smoking-Adjusted Risk Estimates in a Pooled Analysis of Case-Control Studies

OBJECTIVES: The aim of this study was to explore lung cancer risk among firefighters, with adjustment for smoking. METHODS: We used pooled information from the SYNERGY project including 14 case-control studies conducted in Europe, Canada, New Zealand, and China, with lifetime work histories and smoking habits for 14,748 cases of lung cancer and 17,543 controls. We estimated odds ratios by unconditional logistic regression with adjustment for smoking and having ever been employed in a job known to present an excess risk of lung cancer. RESULTS: There was no increased lung cancer risk overall or by specific cell type among firefighters (n = 190), neither before nor after smoking adjustment. We observed no significant exposure-response relationship in terms of work duration. CONCLUSIONS: We found no evidence of an excess lung cancer risk related to occupational exposure as a firefighter