Chronic administration of aripiprazole activates GSK3β-dependent signalling pathways and up-regulates GABAA receptor expression and CREB1 activity in rats

Aripiprazole is a D2-like receptor (D2R) partial agonist with a favourable clinical profile. Previous investigations indicated that acute and short-term administration of aripiprazole had effects on PKA activity, GSK3β-dependent pathways, GABAA receptors, NMDA receptor and CREB1 in the brain. Since antipsychotics are used chronically in clinics, the present study investigated the long-term effects of chronic oral aripiprazole treatment on these cellular signalling pathways, in comparison with haloperidol (a D2R antagonist) and bifeprunox (a potent D2R partial agonist). We found that the Akt-GSK3β pathway was activated by aripiprazole and bifeprunox in the prefrontal cortex; NMDA NR2A levels were reduced by aripiprazole and haloperidol. In the nucleus accumbens, all three drugs increased Akt-GSK3β signalling; in addition, both aripiprazole and haloperidol, but not bifeprunox, increased the expression of Dvl-3, β-catenin and GABAA receptors, NMDA receptor subunits, as well as CREB1 phosphorylation levels. The results suggest that chronic oral administration of aripiprazole affects schizophrenia-related cellular signalling pathways and markers (including Akt-GSK3β signalling, Dvl-GSK3β-β-catenin signalling, GABAA receptor, NMDA receptor and CREB1) in a brain-region-dependent manner; the selective effects of aripiprazole on these signalling pathways might be associated with its unique clinical effects

A pathophysiological framework of hippocampal dysfunction in ageing and disease

The hippocampal formation has been implicated in a growing number of disorders, from Alzheimer's disease and cognitive ageing to schizophrenia and depression. How can the hippocampal formation, a complex circuit that spans the temporal lobes, be involved in a range of such phenotypically diverse and mechanistically distinct disorders? Recent neuroimaging findings indicate that these disorders differentially target distinct subregions of the hippocampal circuit. In addition, some disorders are associated with hippocampal hypometabolism, whereas others show evidence of hypermetabolism. Interpreted in the context of the functional and molecular organization of the hippocampal circuit, these observations give rise to a unified pathophysiological framework of hippocampal dysfunction

Spontaneous and Therapeutic-Induced Mechanisms of Functional Recovery After Stroke

With increasing rates of survival throughout the past several years, stroke remains one of the leading causes of adult disability. Following the onset of stroke, spontaneous mechanisms of recovery at the cellular, molecular, and systems levels ensue. The degree of spontaneous recovery is generally incomplete and variable among individuals. Typically, the best recovery outcomes entail the restitution of function in injured but surviving neural matter. An assortment of restorative therapies exists or is under development with the goal of potentiating restitution of function in damaged areas or in nearby ipsilesional regions by fostering neuroplastic changes, which often rely on mechanisms similar to those observed during spontaneous recovery. Advancements in stroke rehabilitation depend on the elucidation of both spontaneous and therapeutic-driven mechanisms of recovery. Further, the implementation of neural biomarkers in research and clinical settings will enable a multimodal approach to probing brain state and predicting the extent of post-stroke functional recovery. This review will discuss spontaneous and therapeutic-induced mechanisms driving post-stroke functional recovery while underscoring several potential restorative therapies and biomarkers