Schizophrenia is a severe neuropsychiatric disorder with a longstanding history of neurobiological investigation. Although the underlying causal mechanisms remain unknown, early neurodevelopmental ...events have been implicated in pathogenesis, initially by epidemiological and circumstantial data but more recently by brain-specific molecular and genetic findings. Notably, genomic research has recently uncovered discrete risk variants and risk loci associated with schizophrenia, with the potential to elucidate disease mechanisms. This Review revisits the neurodevelopmental model of schizophrenia from a current genetics perspective, delineating the complex genetic basis of the disorder and highlighting gene expression and epigenetic analyses of post-mortem cortical tissue that suggest that early brain development mediates genetic risk associated with schizophrenia. Future functional genomics investigations will accordingly need to characterize schizophrenia risk loci in relevant neurodevelopmental models.
Since a proposal in 1986 that schizophrenia involved early neurodevelopmental deviations beginning in intrauterine life that showed varying expressivity as relevant neural systems matured, our ...understanding of the developmental components of the pathogenesis of schizophrenia has substantially evolved. This commentary highlights recent genetic and epigenetic evidence that prenatal development is a critical period for the expression of schizophrenia risk. Studies of gene expression have been fairly consistent in showing that genes implicated in schizophrenia show relatively greater expression during fetal than postnatal life. Consistent molecular evidence of early environmental perturbations contributing to risk has emerged from studies of epigenetic marks in the brain genome as potential environmental footprints and these also highlight the prenatal period. Analyses of gene expression in placenta dramatically identify the intrauterine environment as a direct point of impact of a component of schizophrenia genetic risk. Together, the enrichment of transcriptional and epigenetic associations with schizophrenia during fetal life suggest that both genetic and environmental risk for schizophrenia have a particular molecular impact on early development, possibly because of genetic biases in environmental sensitivity.
The widespread use of MRI has led to a wealth of structural and functional anatomical findings in patients with diverse psychiatric disorders that may represent insights into pathobiology. However, ...recent technical reports indicate that data from popular MRI research—particularly structural MRI, resting-state functional MRI, and diffusion tensor imaging—are highly sensitive to common artifacts (e.g., head motion and breathing effects) that may dominate the results. Because these and other important confounders of MRI data (e.g., smoking, body weight, metabolic variations, medical comorbidities, psychoactive drugs, alcohol use, mental state) tend to vary systematically between patient and control groups, the evidence that findings are neurobiologically meaningful is inconclusive and may represent artifacts or epiphenomena of uncertain value. The authors caution that uncritically accepting from study to study findings that may represent fallacies of all sorts carries the risk of misinforming practitioners and patients about biological abnormalities underlying psychiatric illness.
Abstract Objective Schizophrenia results in cognitive impairments as well as positive, negative, and disorganized symptomatology. The present study examines the extent to which these cognitive ...deficits are generalized across domains, potential moderator variables, and whether the pattern of cognitive findings reported in schizophrenia has remained consistent over time and across cultural and geographic variation. Method Relevant publications from 2006 to 2011 were identified through keyword searches in PubMed and an examination of reference lists. Studies were included if they (1) compared the cognitive performance of adult schizophrenia patients and healthy controls, (2) based schizophrenia diagnoses on contemporary diagnostic criteria, (3) reported information sufficient to permit effect size calculation, (4) were reported in English, and (5) reported data for neuropsychological tests falling into at least 3 distinct cognitive domains. A set of 100 non-overlapping studies was identified, and effect sizes (Hedge's g ) were calculated for each cognitive variable. Results Consistent with earlier analyses, patients with schizophrenia scored significantly lower than controls across all cognitive tests and domains (grand mean effect size, g = − 1.03). Patients showed somewhat larger impairments in the domains of processing speed (g = − 1.25) and episodic memory (g = − 1.23). Our results also showed few inconsistencies when grouped by geographic region. Conclusions The present study extends findings from 1980 to 2006 of a substantial, generalized cognitive impairment in schizophrenia, demonstrating that this finding has remained robust over time despite changes in assessment instruments and alterations in diagnostic criteria, and that it manifests similarly in different regions of the world despite linguistic and cultural differences.
The immune system has long been hypothesized to play a role in schizophrenia pathogenesis based on data from diverse disciplines. Recent reports of the identification of schizophrenia-associated ...genetic variants and their initial biological characterization have renewed investigation of the role of the immune system in schizophrenia. In the current review, the plausibility of a role of the immune system in schizophrenia pathogenesis is examined, by revisiting epidemiology, neuroimaging, pharmacology, and developmental biology from a genetics perspective, as well as by synthesizing diverse findings from the emerging and dynamic schizophrenia genomics field. Genetic correlations between schizophrenia and immunological disorders are inconsistent and often contradictory, as are neuroimaging studies of microglia markers. Small therapeutic trials of anti-inflammatory agents targeting immune function have been consistently negative. Some gene expression analyses of post-mortem brains of patients with schizophrenia have reported an upregulation of genes of immune function though others report downregulation, and overall transcriptome profiling to date does not support an upregulation of immune pathways associated with schizophrenia genetic risk. The currently reviewed genetic data do not converge to reveal consistent evidence of the neuroimmune system in schizophrenia pathogenesis, and indeed, a substantive role for the neuroimmune system in schizophrenia has yet to be established.
Genetic discoveries about human brain development and neuropsychiatric syndromes have changed the landscape of psychiatric research. The genotyping of hundreds of thousands of individuals has ...identified many hundreds of genomic regions that are associated with psychiatric diagnoses, and progress is being made in uncovering the specific genes that underlie these statistical associations, although most are still undetermined. While there are great expectations that such genetic discoveries will lead to novel treatments based on fundamental mechanisms of illness, there are important caveats. Individual risk-associated common variants explain only a tiny fraction of individual liability. The degree to which common risk variants represent “core” pathogenic insights is controversial. Individuals with rare and more penetrant risk variants are often intellectually disabled, which raises epistemological questions about classification. In clinical research, the application of polygenic risk scores—the cumulative sum of associated alleles in an individual genome—to prediction models of environmental influences and outcome is gaining enthusiasm because these scores explain more liability, but predictions are small and not yet actionable for individuals. Psychiatry is intertwined with genomic medicine, and our understanding of what we call schizophrenia and the possibilities of improving the lives of affected individuals have never seemed more promising. Yet the research challenges are daunting; psychiatric syndromes ultimately reflect how the brain mishandles environmental information, which at the systems level is far “downstream” of the effect of genes in cells.
Recent advances in 3D culture systems have led to the generation of brain organoids that resemble different human brain regions; however, a 3D organoid model of the midbrain containing functional ...midbrain dopaminergic (mDA) neurons has not been reported. We developed a method to differentiate human pluripotent stem cells into a large multicellular organoid-like structure that contains distinct layers of neuronal cells expressing characteristic markers of human midbrain. Importantly, we detected electrically active and functionally mature mDA neurons and dopamine production in our 3D midbrain-like organoids (MLOs). In contrast to human mDA neurons generated using 2D methods or MLOs generated from mouse embryonic stem cells, our human MLOs produced neuromelanin-like granules that were structurally similar to those isolated from human substantia nigra tissues. Thus our MLOs bearing features of the human midbrain may provide a tractable in vitro system to study the human midbrain and its related diseases.
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•Self-organizing midbrain-like organoids (hMLOs) develop from hPSCs in 3D culture•hMLOs, but not mouse MLOs or human cerebral organoids, produce neuromelanin•hMLOs secrete dopamine (DA) and neurons within the hMLOs form functional synapses•Neurons within hMLOs exhibit SNpc DA neuron-like electrophysiological properties
Jo et al. report a method for generating human midbrain-like organoids (hMLOs) from hPSCs in 3D culture. The hMLOs contain distinct layers of neuronal cells expressing human midbrain markers, such as neuromelanin, are electrically active, form functional synapses, and produce dopamine, suggesting that they may be useful for studying human midbrain.
How extrinsic stimuli and intrinsic factors interact to regulate continuous neurogenesis in the postnatal mammalian brain is unknown. Here we show that regulation of dendritic development of newborn ...neurons by Disrupted-in-Schizophrenia 1 (DISC1) during adult hippocampal neurogenesis requires neurotransmitter GABA-induced, NKCC1-dependent depolarization through a convergence onto the AKT-mTOR pathway. In contrast, DISC1 fails to modulate early-postnatal hippocampal neurogenesis when conversion of GABA-induced depolarization to hyperpolarization is accelerated. Extending the period of GABA-induced depolarization or maternal deprivation stress restores DISC1-dependent dendritic regulation through mTOR pathway during early-postnatal hippocampal neurogenesis. Furthermore, DISC1 and NKCC1 interact epistatically to affect risk for schizophrenia in two independent case control studies. Our study uncovers an interplay between intrinsic DISC1 and extrinsic GABA signaling, two schizophrenia susceptibility pathways, in controlling neurogenesis and suggests critical roles of developmental tempo and experience in manifesting the impact of susceptibility genes on neuronal development and risk for mental disorders.
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► DISC1 regulation of dendritic growth requires NKCC1 and depolarizing GABA signaling ► Early-postnatal and adult neurogenesis exhibit differential DISC1 dependency ► Stress synergizes with DISC1 in regulating early-postnatal hippocampal neurogenesis ► Epistatic interaction between DISC1 and NKCC1 affects risk for schizophrenia
Dendritic development in immature neurons depends on combined signals from DISC and the neurotransmitter GABA. SNPs in genes affecting both pathways interact to increase risk of schizophrenia, suggesting that signaling important for the timing of neuronal development is critical in disease manifestation.
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