Present and future antipsychotic drugs: A systematic review of the putative mechanisms of action for efficacy and a critical appraisal under a translational perspective

: Antipsychotics represent the mainstay of schizophrenia pharmacological therapy, and their role has been expanded in the last years to mood disorders treatment. Although introduced in 1952, many years of research were required before an accurate picture of how antipsychotics work began to emerge. Despite the well-recognized characterization of antipsychotics in typical and atypical based on their liability to induce motor adverse events, their main action at dopamine D2R to elicit the "anti-psychotic" effect, as well as the multimodal action at other classes of receptors, their effects on intracellular mechanisms starting with receptor occupancy is still not completely understood. Significant lines of evidence converge on the impact of these compounds on multiple molecular signaling pathways implicated in the regulation of early genes and growth factors, dendritic spine shape, brain inflammation, and immune response, tuning overall the function and architecture of the synapse. Here we present, based on PRISMA approach, a comprehensive and systematic review of the above mechanisms under a translational perspective to disentangle those intracellular actions and signaling that may underline clinically relevant effects and represent potential targets for further innovative strategies in antipsychotic therapy

Transcriptional Signatures of Cognitive Impairment in Rat Exposed to Prenatal Stress

Exposure to adverse events during gestation has detrimental effects on the maturation of specific brain networks, triggering changes in the expression of several stress-related mechanisms that may lead to long-lasting functional consequences, including cognitive deterioration. On these bases, the aim of the present study was to investigate the effects of early-life stress exposure on cognition and to explore potential molecular mechanisms contributing to the long-term functional impairment. We found that exposure to prenatal stress, a well-established animal model of early-life adversity, produces a significant disruption in the novel object recognition test both in male and female adult rats, although such impairment was more pronounced in females. Furthermore, the cognitive dysfunction observed during the behavioral test appears to be sustained by a disrupted activation of key networks of genes that may be required for proper cognitive performance. In particular, within the dorsal hippocampus, a brain region critical for cognition, the glucocorticoid, the inflammatory, and the protein kinase A signaling pathways are regulated by the novel object recognition test in an opposite manner in animals previously exposed to prenatal stress, when compared with control animals. These data further support the evidence that early-life stress exposure prompts cognitive impairment and suggest that this is the consequence of inability to activate the proper transcriptional machinery required for the cognitive performance

Towards Novel Treatments for Schizophrenia: Molecular and Behavioural Signatures of the Psychotropic Agent SEP-363856

Schizophrenia is a complex psychopathology whose treatment is still challenging. Given the limitations of existing antipsychotics, there is urgent need for novel drugs with fewer side effects. SEP-363856 (SEP-856) is a novel psychotropic agent currently under phase III clinical investigation for schizophrenia treatment. In this study, we investigated the ability of an acute oral SEP-856 administration to modulate the functional activity of specific brain regions at basal levels and under glutamatergic or dopaminergic-perturbed conditions in adult rats. We found that immediate-early genes (IEGs) expression was strongly upregulated in the prefrontal cortex and, to a less extent, in the ventral hippocampus, suggesting an activation of these regions. Furthermore, SEP-856 was effective in preventing the hyperactivity induced by an acute injection of phencyclidine (PCP), but not of d-amphetamine (AMPH). The compound effectively normalized the PCP-induced increase in IEGs expression in the PFC at all doses tested, whereas only the highest dose determined the major modulations on AMPH-induced changes. Lastly, SEP-856 acute administration corrected the cognitive deficits produced by subchronic PCP administration. Taken together, our data provide further insights on SEP-856, suggesting that modulation of the PFC may represent an important mechanism for the functional and behavioural activity of this novel compound

The Long-Term Effects of Early Life Stress on the Modulation of miR-19 Levels

MicroRNAs (miRNAs), one of the major small non-coding RNA classes, have been proposed as regulatory molecules in neurodevelopment and stress response. Although alterations in miRNAs profiles have been implicated in several psychiatric and neurodevelopmental disorders, the contribution of individual miRNAs in brain development and function is still unknown. Recent studies have identified miR-19 as a key regulator of brain trajectories, since it drives the differentiation of neural stem cells into mature neurons. However, no findings are available on how vulnerability factors for these disorders, such as early life stress (ELS), can modulate the expression of miR-19 and its target genes. To reach our aim, we investigated miR-19 modulation in human hippocampal progenitor stem cells (HPCs) treated with cortisol during 3 days of proliferation and harvested immediately after the end of the treatment or after 20 days of differentiation into mature neurons. We also analyzed the long-term expression changes of miR-19 and of its validated target genes, involved in neurodevelopment and inflammation, in the hippocampus of adult rats exposed or not to prenatal stress (PNS). Interestingly, we observed a significant downregulation of miR-19 levels both in proliferating (FC = 121.59, p-value = 0.022 for miR-19a; FC = 121.79, p-value = 0.016 for miR-19b) as well as differentiated HPCs (FC = 121.28, p-value = 0.065 for miR-19a; FC = 121.75, p-value = 0.047 for miR-19b) treated with cortisol. Similarly, we found a long-term decrease of miR-19 levels in the hippocampus of adult PNS rats (FC = 121.35, p-value = 0.025 for miR-19a; FC = 121.43, p-value = 0.032 for miR-19b). Among all the validated target genes, we observed a significant increase of NRCAM (FC = 1.20, p-value = 0.027), IL4R (FC = 1.26, p-value = 0.046), and RAPGEF2 (FC = 1.23, p-value = 0.020).We suggest that ELS can cause a long-term downregulation of miR-19 levels, which may be responsible of alterations in neurodevelopmental pathways and in immune/inflammatory processes, leading to an enhanced risk for mental disorders later in life. Intervention strategies targeting miR-19 may prevent alterations in these pathways, reducing the ELS-related effects

Prenatal N-acetyl-cysteine administration prevents social anxiety and modulates brain immune- and plasticity-related genes in adolescent offspring born from high-fat diet C57Bl6/N mouse dams

Aims Maternal obesity is associated to increased oxidative stress (OS) representing a risk factor for adult mental health however the mechanisms underlying the negative long-term effects are poorly understood. We investigated inflammation, OS and hypothalamic-pituitary-adrenal (HPA) axis function in a mouse model of maternal high-fat diet (HFD) as potential mechanisms affecting brain development and emotional behaviour in the offspring. We also tested the antioxidant N-acetyl-cysteine (NAC) in preventing the long-term effects of HFD consumption during pregnancy. Methods Female C57BL/6N mice were fed HFD before and during pregnancy (13 weeks); after 5 weeks, half of them received NAC (1g/kg) for 8 weeks. Emotionality and social behaviour of male and female adolescent offspring (35-45 days) were assessed through the elevated plus maze (EPM) and the social interaction test (SIT); plasma corticosterone levels were assessed under basal conditions and following an acute stress. Gene expression levels of CD68, Bdnf and Nrf2 were measured in hippocampus as markers of microglial activation, brain plasticity and antioxidant capacity respectively by RealTime PCR. We focused on adolescence, an age of vulnerability for the onset of psychopathology. Results HFD offspring showed reduced exploration in the EPM and sociability in the SIT. These effects were associated to decreased hippocampal Bdnf levels in females while males showed increased CD68 expression and reduced basal corticosterone levels. Prenatal NAC administration prevented social anxiety, restored HPA axis basal activity in males and Bdnf levels in females. These effects may be partly mediated by Nrf2, an important regulator of antioxidant defence, as indicated by its upregulation in the hippocampus of both sexes. Conclusions Prenatal HFD showed detrimental sex-dependent effects on brain, neuroendocrine function and emotional behaviour; these changes were buffered by prenatal NAC suggesting that immune and OS signalling may play an important role in foetal programming of adult diseases. Funding: ERANET-NEURON-JTC-2018 Project EMBE

Vulnerability and resilience to prenatal stress exposure: behavioral and molecular characterization in adolescent rats

Abstract Exposure to stress can lead to long lasting behavioral and neurobiological consequences, which may enhance the susceptibility for the onset of mental disorders. However, there are significant individual differences in the outcome of stress exposure since only a percentage of exposed individuals may show pathological consequences, whereas others appear to be resilient. In this study, we aimed to characterize the effects of prenatal stress (PNS) exposure in rats at adolescence and to identify subgroup of animals with a differential response to the gestational manipulation. PNS adolescent offspring (regardless of sex) showed impaired emotionality in different pathological domains, such as anhedonia, anxiety, and sociability. However, using cluster analysis of the behavioral data we could identify 70% of PNS-exposed animals as vulnerable (PNS-vul), whereas the remaining 30% were considered resilient (PNS-res). At the molecular level, we found that PNS-res males show a reduced basal activation of the ventral hippocampus whereas other regions, such as amygdala and dorsal hippocampus, show significant PNS-induced changes regardless from vulnerability or resilience. Taken together, our results provide evidence of the variability in the behavioral and neurobiological effects of PNS-exposed offspring at adolescence. While these data may advance our understanding of the association between exposure to stress during gestation and the risk for psychopathology, the investigation of the mechanisms associated to stress vulnerability or resilience may be instrumental to develop novel strategies for therapeutic intervention

Cross-species evidence from human and rat brain transcriptome for growth factor signaling pathway dysregulation in major depression

An enhanced understanding of the pathophysiology of depression would facilitate the discovery of new efficacious medications. To this end, we examined hippocampal transcriptional changes in rat models of disease and in humans to identify common disease signatures by using a new algorithm for signature-based clustering of expression profiles. The tool identified a transcriptomic signature comprising 70 probesets able to discriminate depression models from controls in both Flinders Sensitive Line and Learned Helplessness animals. To identify disease-relevant pathways, we constructed an expanded protein network based on signature gene products and performed functional annotation analysis. We applied the same workflow to transcriptomic profiles of depressed patients. Remarkably, a 171-probesets transcriptional signature which discriminated depressed from healthy subjects was identified. Rat and human signatures shared the SCARA5 gene, while the respective networks derived from protein-based significant interactions with signature genes contained 25 overlapping genes. The comparison between the most enriched pathways in the rat and human signature networks identified a highly significant overlap (p-value: 3.85 7 10\u20136) of 67 terms including ErbB, neurotrophin, FGF, IGF, and VEGF signaling, immune responses and insulin and leptin signaling. In conclusion, this study allowed the identification of a hippocampal transcriptional signature of resilient or susceptible responses in rat MDD models which overlapped with gene expression alterations observed in depressed patients. These findings are consistent with a loss of hippocampal neural plasticity mediated by altered levels of growth factors and increased inflammatory responses causing metabolic impairments as crucial factors in the pathophysiology of MDD