Short-term succinic acid treatment mitigates cerebellar mitochondrial OXPHOS dysfunction, neurodegeneration and ataxia in a Purkinje-specific spinocerebellar ataxia type 1 (SCA1) mouse model.

Mitochondrial dysfunction plays a significant role in neurodegenerative disease including ataxias and other movement disorders, particularly those marked by progressive degeneration in the cerebellum. In this study, we investigate the role of mitochondrial oxidative phosphorylation (OXPHOS) deficits in cerebellar tissue of a Purkinje cell-driven spinocerebellar ataxia type 1 (SCA1) mouse. Using RNA sequencing transcriptomics, OXPHOS complex assembly analysis and oxygen consumption assays, we report that in the presence of mutant polyglutamine-expanded ataxin-1, SCA1 mice display deficits in cerebellar OXPHOS complex I (NADH-coenzyme Q oxidoreductase). Complex I genes are upregulated at the time of symptom onset and upregulation persists into late stage disease; yet, functional assembly of complex I macromolecules are diminished and oxygen respiration through complex I is reduced. Acute treatment of postsymptomatic SCA1 mice with succinic acid, a complex II (succinate dehydrogenase) electron donor to bypass complex I dysfunction, ameliorated cerebellar OXPHOS dysfunction, reduced cerebellar pathology and improved motor behavior. Thus, exploration of mitochondrial dysfunction and its role in neurodegenerative ataxias, and warrants further investigation

Dopaminergic neurotransmission in the nucleus accumbens modulates social play behavior in rats.

Social play behavior is a highly rewarding form of social interaction displayed by young mammals. Social play is important for neurobehavioral development and it has been found to be impaired in several developmental psychiatric disorders. In line with the rewarding properties of social play, we have previously identified the nucleus accumbens (NAc) as an important site of action for endocannabinoid and opioid modulation of this behavior. NAc dopamine has a well-known role in certain components of reward processes, such as incentive motivation. However, its contribution to the positive emotional aspects of social interactions is less clear. Therefore, we investigated the role of dopaminergic neurotransmission in the NAc in social play behavior in rats. We found that intra-NAc infusion of the dopamine releaser/reuptake inhibitor amphetamine increased social play behavior, which was dependent on activation of both D1 and D2 dopamine receptors. This increase in social play behavior was mimicked by intra-NAc infusion of the dopamine receptor agonist apomorphine, but not of the dopamine reuptake inhibitor GBR-12909. Blockade of either D1 or D2 NAc dopamine receptors reduced social play in animals highly motivated to play as a result of longer social isolation before testing. Last, blockade of NAc dopamine receptors prevented the play-enhancing effects of endocannabinoid and opioid receptor stimulation. These findings demonstrate an important modulatory role of NAc dopaminergic neurotransmission in social play. Thus, functional activity in the mesolimbic dopamine pathway plays an important role in adaptive social development, whereas abnormal NAc dopamine function may underlie the social impairments observed in developmental psychiatric disorders such as autism, attention-deficit hyperactivity disorder (ADHD) or early-onset schizophrenia.Neuropsychopharmacology accepted article preview online, 10 February 2016. doi:10.1038/npp.2016.22