A novel microRNA, novel-m009C, regulates methamphetamine rewarding effects.

Methamphetamine (METH) is a widely abused psychostimulant, whose hyper-rewarding property is believed to underlie its addictive effect, but the molecular mechanism regulating this effect remains unclear. We previously reported that decreased expression of a novel microRNA (miRNA), novel-m009C, is implicated in the regulation of METH hyperlocomotion. Here, we found that novel-m009C may be homologous to hsa-miR-604. Its expression is consistently downregulated in the nucleus accumbens (NAc) of mice when exposed to METH and cocaine, whereas significant alterations in novel-m009C expression were not observed in the NAc of mice subjected to other rewarding and psychiatric stimuli, such as sucrose, morphine and MK-801. We further found the substantial reduction in novel-m009C expression may be regulated by both dopamine receptor D1 (D1R) and D2 (D2R). Increasing novel-m009C levels in the NAc attenuated METH-induced conditioned place preference (CPP) and hyperlocomotion, whereas inhibiting novel-m009C expression in the NAc enhanced these effects but did not change the preference of mice for a natural reward, i.e., sucrose. These effects may involve targeting of genes important for the synaptic transmission, such as Grin1 (NMDAR subunit 1). Our findings demonstrate an important role for NAc novel-m009C in regulating METH reward, reveal a novel molecular regulator of the actions of METH on brain reward circuitries and provide a new strategy for treating METH addiction based on the modulation of small non-coding RNAs.

Regulation of miR-128 in the nucleus accumbens affects methamphetamine-induced behavioral sensitization by modulating proteins involved in neuroplasticity.

Methamphetamine (METH) -induced behavioral sensitization depends on long-term neuroplasticity in the mesolimbic dopamine system, especially in the nucleus accumbens (NAc). miR-128, a brain enriched miRNA, was found to have abilities in regulating neuronal excitability and formation of fear-extinction memory. Here, we aim to identify the role of miR-128 on METH-induced locomotor sensitization of male mice. We identified a significant increase of miR-128 in the NAc of mice upon repeated-intermittent METH exposure but not acute METH administration. Microinjection of adeno-associated virus (AAV)-miR-128 over-expression and inhibition constructs into the NAc of mice resulted in enhanced METH-induced locomotor sensitization and attenuated effects of METH respectively. Isobaric tags for relative and absolute quantification (iTRAQ) technology and ingenuity pathway analysis (IPA) were carried out to uncover the potential molecular mechanisms underlying miR-128-regulated METH sensitization. Differentially expressed proteins, including 25 potential targets for miR-128 were annotated in regulatory pathways that modulate dendritic spines, synaptic transmission and neuritogenesis. Of which, Arf6, Cpeb3 and Nlgn1, were found to be participating in miR-128-regulated METH sensitization. Consistently, METH-induced abnormal changes of Arf6, Cpeb3 and Nlgn1 in the NAc of mice were also detected by qPCR and validated by western blot analysis. Thus, miR-128 may contribute to METH sensitization through controlling neuroplasticity. Our study suggested miR-128 was an important regulator of METH- induced sensitization and also provided the potential molecular networks of miR-128 in regulating METH-induced sensitization.

Voltage-gated calcium channel activity and complex related genes and schizophrenia: A systematic investigation based on Han Chinese population.

Schizophrenia (SCZ) is a devastating mental disorder affecting approximately 1% of the worldwide population. Early studies have indicated that genetics plays an important role in the onset and development of SCZ. Accumulating evidence supports that SCZ is linked to abnormalities of synapse transmission and synaptic plasticity. Voltage-gated calcium channel (VGCC) subunits are critical for mediating intracellular Ca2 + influx and therefore are responsible for changing neuronal excitability and synaptic plasticity. To systematically investigate the role of calcium signaling genes in SCZ susceptibility, we conducted a case-control study that included 2518 SCZ patients and 7521 healthy controls with Chinese Han ancestry. Thirty-seven VGCC genes, including 363 tag single nucleotide polymorphisms (SNPs), were examined. Our study replicated the following previously identified susceptible loci: CACNA1C, CACNB2, OPRM1, GRM7 and PDE4B. In addition, several novel loci including CACNA2D1, PDE4D, NALCN, and CACNA2D3 were also identified to be associated with SCZ in our Han Chinese sample. Combined with GTEx eQTL data, we have shown that CASQ2, ITGAV, and TMC2 can be also added into the prioritization list of SCZ susceptible genes. Two-way interaction analyses identified widespread gene-by-gene interactions among VGCC activity and complex-related genes for the susceptibility of SCZ. Further sequencing based studies are still needed to unravel potential contributions of schizophrenia risk from rare or low frequency variants of these candidate genes.

Relationship between schizophrenia and changes in the expression of the long non-coding RNAs Meg3, Miat, Neat1 and Neat2.

Schizophrenia (SZ) is a complex disease caused by multiple factors. The development of the disease is mediated by a number of neural growth and development factors, suggesting that extensive changes in nerve structure and abnormal expression of genes in some important signalling pathways occur. Based on accumulating evidence, long non-coding RNAs (lncRNAs) play a crucial role in regulating neural diseases, including SZ. In the current study, we used mouse models of methamphetamine (METH) - and MK801-induced SZ to investigate changes in the expression of four lncRNAs (Meg3, Miat, Neat1 and Neat2) in the prefrontal cortex (PFC). Miat and Neat2 expression was significantly decreased in the PFC of the SZ model mice, regardless of whether the disease was induced by MK801 or METH. We further measured the levels of these lncRNAs in the peripheral blood (PB) collected from treated and untreated patients with SZ and from healthy controls. Neat1 and Neat2 levels were significantly decreased in the PB of untreated patients with SZ, but the trends in the expression of these lncRNAs nearly reached a normal level in treated patients with SZ. In conclusion, Neat2 and Miat may function as important regulators of SZ. Our findings provide important clues for new targets of lncRNAs that are involved in SZ.

Maternal methamphetamine exposure causes cognitive impairment and alteration of neurodevelopment-related genes in adult offspring mice.

Prenatal drug exposure altered cognitive function in individuals, and may also impact their offspring's susceptibility to cognitive impairment. The high incidence of methamphetamine (METH) abuse among adolescents and women of childbearing age elevates the importance to determine the influence of maternal METH exposure on cognitive functions in the descendants. We hypothesized that maternal METH exposure affects cognitive behavior in offspring mice by disrupting gene expression associated with neural development. Here, female C57BL/6 mice were exposed to intermittent escalating doses of METH or saline from adolescence to adulthood, and then continued through pregnancy. Interestingly, male but not female offspring exhibited impaired short-term recognition memory and long-term spatial memory retention in novel object recognition and Morris water maze test respectively. Additionally, maternal METH exposure altered neurodevelopmental genes in both male and female offspring, and 12 differentially expressed genes between male and female were observed in the HPC and NAc regions. These differentially expressed genes are involved in neurogenesis, axon guidance, neuron migration and synapse of neural development circuits. Our observations suggest that maternal METH exposure induced differential expression patterns of neurodevelopment-related genes in the HPC and NAc of male and female mice, which may underlie the different cognitive behavior phenotypes in both genders.