Alterations in intracellular signaling pathways are important in treating complex neuropsychiatric disorders 1 . Signaling pathway components, including several protein kinases and phosphatases, are direct targets of some of the most effective medications for treating these disorders. For example, lithium, one of the most established treatments for bipolar disorder (BPD), is believed to exert its therapeutic effects by directly modulating the activity of inositol monophosphatase and of glycogen synthase kinase 3β (GSK3β) 1 . It is still unclear, however, whether abnormalities in signaling pathways are central to the pathophysiology of psychiatric illnesses, including schizophrenia. Nevertheless, genes regulating such signaling cascades, especially those affecting synaptic transmission and plasticity, are good candidate susceptibility genes. RESULTS Low levels of AKT1 in individuals with schizophreniaIt is well established that most of the central nervous system (CNS) protein kinases and phosphatases are involved in a wide variety of cellular functions and are expressed in diverse cell types including peripheral blood lymphocytes. We speculated that alterations in brain levels or activity of protein kinases and phosphatases may contribute to schizophrenia susceptibility in humans and that this might be observed in the peripheral tissues of individuals with schizophrenia. We examined the abundance of several kinases implicated in synaptic plasticity (PRKACA, AKT1, PRKC, MAP3K, GSK3β, PIK3CB and PIK3R2) 2-4 . We assessed changes in protein levels because they are more likely to be cell-autonomous and less likely to be influenced by the cellular environment when compared, for example, with rapid and reversible activity modifications through phosphorylation. Protein extracts from lymphocyte-derived cell lines from individuals with schizophrenia (n = 28) and unaffected controls (n = 28) were subjected to SDS-PAGE and immunoblot analysis. Levels of protein kinase AKT1 were 68% lower in individuals with schizophrenia than in controls (Fig. 1a, P = 0.014, Mann-Whitney test, corrected for eight tests). In contrast, we observed no differences in the levels of the other kinases tested.This initial exploratory analysis may have been confounded by an imperfect match of cases and controls and the influence of Epstein-Barr virus (EBV) transformation on the levels of AKT1. Nonetheless, the specificity of our findings together with the fact that the same cellular pathway has been implicated in mood disorders 1 prompted us to follow up our initial observation using four complementary approaches. First, we attempted to verify a reduction in AKT1 levels in postmortem frontal cortex, one of the primary sites of disease pathology. Second, we examined whether the reduction in AKT1 levels was reflected by a reduction in substrate phosphorylation in both peripheral lymphocytes and postmortem frontal cortex. Third, we tested whether certain variants of the gene encoding AKT1 were preferentially transmitted in individuals with schizophreni...

Recent reports indicate an association between second trimester human influenza viral infection and later development of schizophrenia. Postmortem human brain studies also provide evidence for reduction in Reelin mRNA (an important secretory protein responsible for normal lamination of the brain) in schizophrenic brains. We hypothesized that human influenza infection in day 9 pregnant mice would alter the expression of reelin in day 0 neonatal brains. Prenatally-infected murine brains from postnatal day 0 showed significant reductions in reelinpositive cell counts in layer I of neocortex and other cortical and hippocampal layers when compared to controls. Whereas layer I Cajal-Retzius cells produced significantly less Reelin in infected animals, the same cells showed normal production of calretinin and nNOS when compared to control brains. Moreover, prenatal viral infection caused decreases in neocortical and hippocampal thickness. These results implicate a potential role of prenatal viral infection in causation of neuronal migration abnormalities via reduction in Reelin production in neonatal brains.

Schizophrenia is a prevalent complex trait disorder manifested by severe neurocognitive dysfunctions and lifelong disability. During the past few years several studies have provided direct evidence for the involvement of different signaling pathways in schizophrenia. In this review, we mainly focus on AKT/GSK3 signaling pathway in schizophrenia. The original study on the involvement of this pathway in schizophrenia was published by Emamian et al. in 2004. This study reported convergent evidence for a decrease in AKT1 protein levels and levels of phosphorylation of GSK-3β in the peripheral lymphocytes and brains of individuals with schizophrenia; a significant association between schizophrenia and an AKT1 haplotype; and a greater sensitivity to the sensorimotor gating-disruptive effect of amphetamine, conferred by AKT1 deficiency. It also showed that haloperidol can induce a stepwise increase in regulatory phosphorylation of AKT1 in the brains of treated mice that could compensate for the impaired function of this signaling pathway in schizophrenia. Following this study, several independent studies were published that not only confirmed the association of this signaling pathway with schizophrenia across different populations, but also shed light on the mechanisms by which AKT/GSK3 pathway may contribute to the development of this complex disorder. In this review, following an introduction on the role of AKT in human diseases and its functions in neuronal and non-neuronal cells, a review on the results of studies published on AKT/GSK3 signaling pathway in schizophrenia after the original 2004 paper will be provided. A brief review on other signaling pathways involved in schizophrenia and the possible connections with AKT/GSK3 signaling pathway will be discussed. Moreover, some possible molecular mechanisms acting through this pathway will be discussed besides the mechanisms by which they may contribute to the pathogenesis of schizophrenia. Finally, different transcription factors related to schizophrenia will be reviewed to see how hypo-activity of AKT signaling pathway may impact such transcriptional mechanisms.

BackgroundSpinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disorder characterized by progressive motor and cognitive dysfunction. Caused by an expanded polyglutamine tract in ataxin 1 (ATXN1), SCA1 pathogenesis involves a multifactorial process that likely begins with misfolding of ATXN1, which has functional consequences on its interactions, leading to transcriptional dysregulation. Because lithium has been shown to exert neuroprotective effects in a variety of conditions, possibly by affecting gene expression, we tested the efficacy of lithium treatment in a knock-in mouse model of SCA1 (Sca1154Q/2Q mice) that replicates many features of the human disease.Methods and Findings Sca1154Q/2Q mice and their wild-type littermates were fed either regular chow or chow that contained 0.2% lithium carbonate. Dietary lithium carbonate supplementation resulted in improvement of motor coordination, learning, and memory in Sca1154Q/2Q mice. Importantly, motor improvement was seen when treatment was initiated both presymptomatically and after symptom onset. Neuropathologically, lithium treatment attenuated the reduction of dendritic branching in mutant hippocampal pyramidal neurons. We also report that lithium treatment restored the levels of isoprenylcysteine carboxyl methyltransferase (Icmt; alternatively, Pccmt), down-regulation of which is an early marker of mutant ATXN1 toxicity.ConclusionsThe effect of lithium on a marker altered early in the course of SCA1 pathogenesis, coupled with its positive effect on multiple behavioral measures and hippocampal neuropathology in an authentic disease model, make it an excellent candidate treatment for human SCA1 patients.