No abstract

Mutations in the DJ-1 gene were recently identified in an autosomal recessive form of early-onset familial Parkinson disease. Structural biology, biochemistry, and cell biology studies have suggested potential functions of DJ-1 in oxidative stress, protein folding, and degradation pathways. However, animal models are needed to determine whether and how loss of DJ-1 function leads to Parkinson disease. We have generated DJ-1 null mice with a mutation that resembles the large deletion mutation reported in patients. Our behavioral analyses indicated that DJ-1 deficiency led to age-dependent and taskdependent motoric behavioral deficits that are detectable by 5 months of age. Unbiased stereological studies did not find obvious dopamine neuron loss in 6-month-and 11-month-old mice. Neurochemical examination revealed significant changes in striatal dopaminergic function consisting of increased dopamine reuptake rates and elevated tissue dopamine content. These data represent the in vivo evidence that loss of DJ-1 function alters nigrostriatal dopaminergic function and produces motor deficits.Mutations in DJ-1 were recently identified in an autosomal recessive form of early-onset familial Parkinson disease (PD) 1 (1). The first reported mutation involves one large deletion of the first 5 exons and part of the promoter and another mutation was a missense mutation (L166P) that might cause instability of the DJ-1 protein by preventing it from folding properly and forming homodimers (2-5). Since this first report, a number of other mutations of DJ-1 including deletion mutations, point mutations, and a frameshift mutation have been found to cause PD (6 -10). These studies suggest that the loss of the normal function of DJ-1 leads to PD.However, the nature of the normal function of DJ-1 and the mechanism by which DJ-1 deficiency leads to PD are not well established. Studies prior to the report of its association with PD suggested that DJ-1 might play a role in oncogenesis (11), male fertility (12, 13), control of protein-RNA interaction (14), and in modulating androgen receptor transcription activity (15,16). In addition, the DJ-1 protein was shown to be responsive to oxidation (17, 18), suggesting a potential role in oxidative stress, a process often implicated in PD. Studies on PD-linked DJ-1 mutations indicate that wild-type, but not mutant, DJ-1 protects cells from oxidative stress (19 -21). Canet-Aviles et al. (22) reported that oxidation of the Cys 106 residue in DJ-1 could lead to its relocalization in mitochondria and protect cells from mitochondrial damage. Structurally, DJ-1 closely resembles the members of the ThiJ/PfpI family that have protease and chaperone activities (23-27). Recent biochemical studies suggested that DJ-1 might have protease (5) and redox-dependent chaperone activities (28). Therefore, putative functions of DJ-1 seem to converge on the common pathogenesis of PD implicated in other genetic and sporadic forms of PD.Despite those new insights into the biochemical and cellular functions of DJ-1, th...

Attention-deficit hyperactivity disorder (ADHD) is estimated to affect 8-12% of school-age children worldwide. ADHD is a complex disorder with significant genetic contributions. However, no single gene has been linked to a significant percentage of cases, suggesting that environmental factors may contribute to ADHD. Here, we used behavioral, molecular, and neurochemical techniques to characterize the effects of developmental exposure to the pyrethroid pesticide deltamethrin. We also used epidemiologic methods to determine whether there is an association between pyrethroid exposure and diagnosis of ADHD. Mice exposed to the pyrethroid pesticide deltamethrin during development exhibit several features reminiscent of ADHD, including elevated dopamine transporter (DAT) levels, hyperactivity, working memory and attention deficits, and impulsive-like behavior. Increased DAT and D1 dopamine receptor levels appear to be responsible for the behavioral deficits. Epidemiologic data reveal that children aged 6-15 with detectable levels of pyrethroid metabolites in their urine were more than twice as likely to be diagnosed with ADHD. Our epidemiologic finding, combined with the recapitulation of ADHD behavior in pesticide-treated mice, provides a mechanistic basis to suggest that developmental pyrethroid exposure is a risk factor for ADHD.

No abstract

Prairie vole breeder pairs form monogamous pair bonds, which are maintained through the expression of selective aggression toward novel conspecifics. Here, we utilize behavioral and anatomical techniques to extend the current understanding of neural mechanisms that mediate pair bond maintenance. For both sexes, we show that pair bonding up-regulates mRNA expression for genes encoding D1-like dopamine (DA) receptors and dynorphin as well as enhances stimulated DA release within the nucleus accumbens (NAc). We next show that D1-like receptor regulation of selective aggression is mediated through downstream activation of kappa-opioid receptors (KORs) and that activation of these receptors mediates social avoidance. Finally, we also identified sex-specific alterations in KOR binding density within the NAc shell of paired males and demonstrate that this alteration contributes to the neuroprotective effect of pair bonding against drug reward. Together, these findings suggest motivational and valence processing systems interact to mediate the maintenance of social bonds.DOI: http://dx.doi.org/10.7554/eLife.15325.001

The DA uptake changes after chronic alcohol exposure documented here using FSCV may be associated with a compensatory response of the DA system aimed at decreasing DA signaling. Alterations in autoreceptor function may require relatively long lasting alcohol exposure.

Brain-derived neurotrophic factor (BDNF) modulates the synaptic transmission of several monoaminergic neuronal systems, including forebrain dopamine-containing neurons. Recent evidence shows a strong correlation between neuropsychiatric disorders and BDNF hypofunction. The aim of the present study was to characterize the effect of low endogenous levels of BDNF on dopamine system function in the caudate-putamen using heterozygous BDNF (BDNF+/−) mice. Apparent extracellular dopamine levels in the caudate-putamen, determined by quantitative microdialysis, were significantly elevated in BDNF+/− mice compared to wildtype controls (12 vs. 5 nM, respectively). BDNF+/− mice also had a potentiated increase in dopamine levels following potassium (120 mM)-stimulation (10-fold) relative to wildtype controls (6-fold). Slice fast-scan cyclic voltammetry revealed that BDNF+/− mice had reductions in both electrically-evoked dopamine release and dopamine uptake rates in the caudate-putamen. Superfusion of BDNF led to partial recovery of the electrically-stimulated dopamine release response in BDNF+/− mice. Conversely, tissue accumulation of L-3,4-dihydroxyphenylalanine, extracellular levels of dopamine metabolites, and spontaneous locomotor activity were unaltered. Together, this study indicates that endogenous BDNF influences dopamine system homeostasis by regulating the release and uptake dynamics of presynaptic dopamine transmission.

Although the vast majority of research on the dopamine system has been performed in rodents, and it is assumed that this work will inform us about the human condition, there have been very few direct comparisons of presynaptic dopamine terminal function across multiple species. Because it is difficult to query rapid sub-second dopamine signaling in humans using voltammetric methods, we chose to compare dopamine signals across multiple striatal subregions in slices from C57BL/6J mice, Sprague–Dawley rats and rhesus macaques. We found a dorsal to ventral gradient of dopamine uptake rates with highest levels in the dorsal striatum and lowest levels in the nucleus accumbens shell, which is conserved across species. In addition to uptake rates, there was also a dorsal to ventral, high to low, gradient in the magnitude of stimulated DA release observed in monkeys, mice, and rats. These data demonstrate that there is considerable functional homology across striatal regions in non-human primates and rodents, lending support to the use of rodents as model systems to study dopamine-related circuitry and disorders that are clinically relevant to the human population.