Differential Alterations in Striatal Direct and Indirect Pathways Mediate Two Autism-like Behaviors in Valproate-Exposed Mice.

Autism is characterized by two key diagnostic criteria including social deficits and repetitive behaviors. Although recent studies implicated ventral striatum in social deficits and dorsal striatum in repetitive behaviors, here we revealed coexisting and opposite morphologic and functional alterations in the dorsostriatal direct and indirect pathways, and such alterations in these two pathways were found to be responsible, respectively, for the two abovementioned different autism-like behaviors exhibited by male mice prenatally exposed to valproate. The alteration in direct pathway was characterized by a potentiated state of basal activity, with impairment in transient responsiveness of D1-MSNs during social exploration. Concurrent alteration in indirect pathway was a depressed state of basal activity, with enhancement in transient responsiveness of D2-MSNs during repetitive behaviors. A causal relationship linking such differential alterations in these two pathways to the coexistence of these two autism-like behaviors was demonstrated by the cell type-specific correction of abnormal basal activity in the D1-MSNs and D2-MSNs of valproate-exposed mice. The findings support those differential alterations in two striatal pathways mediate the two coexisting autism-like behavioral abnormalities, respectively. This result will help in developing therapeutic options targeting these circuit alterations.SIGNIFICANCE STATEMENT Autism is characterized by two key diagnostic criteria including social deficits and repetitive behaviors. Although a number of recent studies have implicated ventral striatum in social deficits and dorsal striatum in repetitive behaviors, but social behaviors need to be processed by a series of actions, and repetitive behaviors, especially the high-order repetitive behaviors such as restrictive interests, have its scope to cognitive and emotional domains. The current study, for the first time, revealed that prenatal valproate exposure induced coexisting and differential alterations in the dorsomedial striatal direct and indirect pathways, and that these alterations mediate the two coexisting autism-like behavioral abnormalities, respectively. This result will help in developing therapeutic options targeting these circuit alterations to address the behavioral abnormalities.

Cisd2 is essential to delaying cardiac aging and to maintaining heart functions.

CDGSH iron-sulfur domain-containing protein 2 (Cisd2) is pivotal to mitochondrial integrity and intracellular Ca2+ homeostasis. In the heart of Cisd2 knockout mice, Cisd2 deficiency causes intercalated disc defects and leads to degeneration of the mitochondria and sarcomeres, thereby impairing its electromechanical functioning. Furthermore, Cisd2 deficiency disrupts Ca2+ homeostasis via dysregulation of sarco/endoplasmic reticulum Ca2+-ATPase (Serca2a) activity, resulting in an increased level of basal cytosolic Ca2+ and mitochondrial Ca2+ overload in cardiomyocytes. Most strikingly, in Cisd2 transgenic mice, a persistently high level of Cisd2 is sufficient to delay cardiac aging and attenuate age-related structural defects and functional decline. In addition, it results in a younger cardiac transcriptome pattern during old age. Our findings indicate that Cisd2 plays an essential role in cardiac aging and in the heart's electromechanical functioning. They highlight Cisd2 as a novel drug target when developing therapies to delay cardiac aging and ameliorate age-related cardiac dysfunction.

The Association between 5-Hydroxytryptamine Receptor 1B rs13212041 Polymorphism and Trait Anxiety in Chinese Han College Subjects.

Trait anxiety is a vulnerable personality factor for anxiety and depression. High levels of trait anxiety confer an elevated risk for the development of anxiety and other psychiatric disorders. There is evidence that 5-hydroxytryptamine receptor 1B (5-HT1B) gene polymorphisms play an important role in emotional disorders. Genotyping for four single-nucleotide polymorphisms (SNP) (rs11568817, rs130058, rs6297, and rs13212041) was conducted for 388 high trait anxious (HTA) individuals and 463 low traitanxious (LTA) individuals in Chinese Han college subjects. The results showed that the frequencies of the C-allele and TC + CC genotype of rs13212041 in the LTA individuals were higher than that in the HTA individuals (p = 0.025 and p = 0.014, respectively). Both the C-allele and TC + CC genotype were associated with trait anxiety decreasing (OR = 0.771 and OR = 0.71, respectively). Furthermore, different gene model analysis also showed that the C allele was a protective factor for trait anxiety in Chinese Han college subjects. These findings suggest that 5-HT1B rs13212014 may play a role in trait anxiety among China Han college subjects. The rs13212014 polymorphism may be involved in decreasing the risk of trait anxiety. These results also provide a novel insight into the molecular mechanism underlying trait anxiety.