Genetic insights into the neurodevelopmental origins of schizophrenia

Abstract

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.

Cannabinoid–glutamate interactions and neural oscillations: implications for psychosis

“…While the focus was based on pharmacological models of psychosis using THC and ketamine, the hypotheses put forth have implications for SZ proper, as part of the pathophysiology of this disorder involves abnormalities of both the cannabinoid and glutamatergic systems (see above). The idea that multiple neurotransmitter systems are involved in SZ is in line with current conceptualizations of SZ as a polygenetic disorder, involving numerous neurotransmitter and neuromodulatory systems (Birnbaum & Weinberger, ). The converging evidence implicating CB1Rs, NMDARs and neural oscillations in psychosis is consistent with this notion and therefore provides a backdrop for a series of intriguing future research directions.…”

Expression of vasopressin mRNA in the hypothalamus of individuals with a diagnosis of schizophrenia

“…Schizophrenia is a complex neurobiological disorder in which genetic, developmental, and environmental factors have been identified to play a role (Birnbaum & Weinberger, 2017;Keller, 2018). The final pathophysiology involves a dysregulation of dopaminergic, glutamatergic, GABAergic, and cholinergic neurotransmitter systems and their interactions (Siever & Davis, 2004).…”

“…Schizophrenia is a major psychiatric disorder with an unknown causative pathophysiology (Birnbaum & Weinberger, 2017). Stress could be a factor in the pathophysiology of the disease, and that might involve the endocrine hypothalamic-pituitary-adrenal axis.…”

Research Domain Criteria: Cutting Edge Neuroscience or Galen’s Humors Revisited?

“…We contend that these disorders are best conceptualized not as extremes of normal, but rather according to the disease model, in which they are the result of etiologic and pathogenic processes that disturb the normal development and function of the brain and result in a disease with a distinct natural history. Even accepting the current RDoC domains and constructs as valid descriptions of normal brain processes (a debated assumption [10-12]), the available clinical, genetic, and imaging data suggest distinct differences between disease and normal states (e.g., in schizophrenia [12, 13]). Psychiatric diseases, like other diseases in medicine, represent a disruption of normal neuropsychological and brain function, a break from normal.…”