The miR-124-AMPAR pathway connects polygenic risks with behavioral changes shared between schizophrenia and bipolar disorder.

Schizophrenia (SZ) and bipolar disorder (BP) are highly heritable major psychiatric disorders that share a substantial portion of genetic risk as well as their clinical manifestations. This raises a fundamental question of whether, and how, common neurobiological pathways translate their shared polygenic risks into shared clinical manifestations. This study shows the miR-124-3p-AMPAR pathway as a key common neurobiological mediator that connects polygenic risks with behavioral changes shared between these two psychotic disorders. We discovered the upregulation of miR-124-3p in neuronal cells and the postmortem prefrontal cortex from both SZ and BP patients. Intriguingly, the upregulation is associated with the polygenic risks shared between these two disorders. Seeking mechanistic dissection, we generated a mouse model that upregulates miR-124-3p in the medial prefrontal cortex. We demonstrated that the upregulation of miR-124-3p increases GRIA2-lacking calcium-permeable AMPARs and perturbs AMPAR-mediated excitatory synaptic transmission, leading to deficits in the behavioral dimensions shared between SZ and BP.

Elevated body fat increases amphetamine accumulation in brain: evidence from genetic and diet-induced forms of adiposity.

Despite the high prevalence of obesity, little is known about its potential impact on the pharmacokinetics of psychotropic drugs. In the course of investigating the role of the microRNA system on neuronal signaling, we found that mice lacking the translin/trax microRNA-degrading enzyme display an exaggerated locomotor response to amphetamine. As these mice display robust adiposity in the context of normal body weight, we checked whether this phenotype might reflect elevated brain levels of amphetamine. To assess this hypothesis, we compared plasma and brain amphetamine levels of wild type and Tsn KO mice. Furthermore, we checked the effect of diet-induced increases in adiposity on plasma and brain amphetamine levels in wild type mice. Brain amphetamine levels were higher in Tsn KO mice than in wild type littermates and correlated with adiposity. Analysis of the effect of diet-induced increases in adiposity in wild type mice on brain amphetamine levels also demonstrated that brain amphetamine levels correlate with adiposity. Increased adiposity displayed by Tsn KO mice or by wild type mice fed a high-fat diet correlates with elevated brain amphetamine levels. As amphetamine and its analogues are widely used to treat attention deficit disorder, which is associated with obesity, further studies are warranted to assess the impact of adiposity on amphetamine levels in these patients.

Translocator protein (TSPO) and stress cascades in mouse models of psychosis with inflammatory disturbances.

Changes in inflammatory cascades have been implicated in the underlying pathophysiology of psychosis. Translocator protein 18 kDa (TSPO) has been used to assess neuroinflammatory processes in psychotic disorders. Nonetheless, it is unclear whether TSPO, a mitochondrial protein, can be interpreted as a general marker for inflammation in diseases involving psychosis. To address this question, we investigated TSPO signaling in representative mouse models for psychosis with inflammatory disturbances. The maternal immune activation and cuprizone short-term exposure models show different TSPO signaling. Furthermore, we observed similarities and differences in their respective stress pathways including stress hormone signaling and oxidative stress that are functionally interconnected with the inflammatory responses. We propose that more careful studies of TSPO distribution in neuroinflammation and other stress cascades associated with psychotic symptoms will allow us to understand the biological mechanisms underlying psychosis-related behaviors.

Dimensional assessment of behavioral changes in the cuprizone short-term exposure model for psychosis.

Recent clinical studies have suggested a role for immune/inflammatory responses in the pathophysiology of psychosis. However, a mechanistic understanding of this process and its application for drug discovery is underdeveloped. Here we assessed our recently developed cuprizone short-term exposure (CSE) mouse model across behavioral domains targeting neurocognitive and neuroaffective systems. We propose that the CSE model may be useful for understanding the mechanism associating inflammation and psychosis, with applications for drug discovery in that context.

The radical scavenger edaravone counteracts diabetes in multiple low-dose streptozotocin-treated mice.

Edaravone is a potent scavenger of hydroxyl radicals and attenuates oxidative damage-related neurodegenerative diseases. Previous studies suggest that oxidative stress plays a key role in the pathogenesis of diabetes. The present study examined the effect of edaravone on diabetes in multiple low-dose streptozotocin-treated mice. Mice treated with low-doses of streptozotocin for five consecutive days showed progressive hyperglycemia and an increased incidence of diabetes. Daily treatment with edaravone during the streptozotocin injections counteracted the multiple low-dose streptozotocin-induced hyperglycemia in a dose-dependent manner. Edaravone protected against the multiple low-dose streptozotocin-induced reduction in pancreatic insulin. The suppressive effects of edaravone were also observed when it was administered after the last injection of streptozotocin. Histochemical examination showed that multiple low-dose streptozotocin treatment caused mononuclear cell infiltration in pancreatic islets, followed by hyperglycemia, and that edaravone significantly inhibited the multiple low-dose streptozotocin-induced insulitis. Multiple low-dose streptozotocin treatment also increased the lipid peroxidation product thiobarbituric acid reactive substance in pancreatic tissues of mice, and this effect was completely inhibited by edaravone. These findings suggest that edaravone, even after streptozotocin treatment, counteracts the development of multiple low-dose streptozotocin-induced diabetes by scavenging free radicals, which are possible mediators of the immune destruction of islet beta cells.