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...

Individuals with 22q11.2 microdeletions show behavioral and cognitive deficits and are at high risk of developing schizophrenia. We analyzed an engineered mouse strain carrying a chromosomal deficiency spanning a segment syntenic to the human 22q11.2 locus. We uncovered a previously unknown alteration in the biogenesis of microRNAs (miRNAs) and identified a subset of brain miRNAs affected by the microdeletion. We provide evidence that the abnormal miRNA biogenesis emerges because of haploinsufficiency of the Dgcr8 gene, which encodes an RNA-binding moiety of the 'microprocessor' complex and contributes to the behavioral and neuronal deficits associated with the 22q11.2 microdeletion.

Schizophrenia is an etiologically heterogeneous psychiatric disease, which exists in familial and nonfamilial (sporadic) forms. Here, we examine the possibility that rare de novo copy number (CN) mutations with relatively high penetrance contribute to the genetic component of schizophrenia. We carried out a whole-genome scan and implemented a number of steps for finding and confirming CN mutations. Confirmed de novo mutations were significantly associated with schizophrenia (P = 0.00078) and were collectively approximately 8 times more frequent in sporadic (but not familial) cases with schizophrenia than in unaffected controls. In comparison, rare inherited CN mutations were only modestly enriched in sporadic cases. Our results suggest that rare de novo germline mutations contribute to schizophrenia vulnerability in sporadic cases and that rare genetic lesions at many different loci can account, at least in part, for the genetic heterogeneity of this disease.

Abnormalities in functional connectivity between brain areas have been postulated as an important pathophysiological mechanism underlying schizophrenia 1,2 . In particular, macroscopic measurements of brain activity in patients suggest that functional connectivity between the frontal and temporal lobes may be altered 3,4 . However, it remains unclear whether such dysconnectivity relates to the aetiology of the illness, and how it is manifested in the activity of neural circuits. Because schizophrenia has a strong genetic component 5 , animal models of genetic risk factors are likely to aid our understanding of the pathogenesis and pathophysiology of the disease. Here we study Df(16) A +/− mice, which model a microdeletion on human chromosome 22 (22q11.2) that constitutes one of the largest known genetic risk factors for schizophrenia 6 . To examine functional connectivity in these mice, we measured the synchronization of neural activity between the hippocampus and the prefrontal cortex during the performance of a task requiring working memory, which is one of the cognitive functions disrupted in the disease. In wild-type mice, hippocampal-prefrontal synchrony increased during working memory performance, consistent with previous reports in rats7. Df(16) A +/− mice, which are impaired in the acquisition of the task, showed drastically reduced synchrony, measured both by phase-locking of prefrontal cells to hippocampal theta oscillations and by coherence of prefrontal and hippocampal local field potentials. Furthermore, the magnitude of hippocampal-prefrontal coherence at the onset of training could be used to predict the time it took the Df(16)A +/− mice to learn the task and increased more slowly during task acquisition. These data suggest how the deficits in functional connectivity observed in patients with schizophrenia may be realized at the single-neuron level. Our findings further suggest that impaired long-range synchrony of neural activity is one consequence of the 22q11.2 deletion and may be a fundamental component of the pathophysiology underlying schizophrenia.Correspondence and requests for materials should be addressed to J. A. Gordon (jg343@columbia.edu) or J. A. Gogos (jag90@columbia.edu). Supplementary Information is linked to the online version of the paper at www.nature.com/nature. Author Contributions T.S., M.K., J. A. Gogos and J. A. Gordon designed the experiments. T.S. carried out the behavioural and electrophysiology experiments. K.L.S. engineered and supplied the mutant and control mice and contributed to the experimental design. T.S. and J. A. Gordon analysed the data. T.S., M.K., J. A. Gogos and J. A. Gordon interpreted the results and wrote the paper.Author Information Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests. NIH Public Access Author ManuscriptNature. Author manuscript; available in PMC 2010 October 1. Despite decades of research, the neural circuit abnormalities underlying schizophreni...