Novel Insights into Early Schizophrenia Development Revealed Through Scientific Studies

Two groundbreaking studies have leveraged cutting-edge technology to simulate early stages of human brain development with the aim of elucidating the underlying mechanisms of schizophrenia. The inaugural study employed brain organoids to investigate ongoing abnormalities in axonal regulation as a potential initial factor leading to the disorder. The subsequent research centered on the CYFIP1 gene within a particular genetic risk region, underscoring the gene’s putative role in the functioning of microglial cells and its links to neurodevelopmental conditions, including schizophrenia and autism.

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Schizophrenia is a multifaceted neuropsychiatric condition whose complexities have yet to be fully comprehended. Although symptoms generally appear in late adolescence or early adult life, it is theorized that the origin of the disorder can be traced back to irregularities in neurodevelopment. The scarcity of human prenatal and postnatal brain tissue for research has historically impeded the identification of preliminary disease mechanisms, particularly during the pivotal prenatal phase.

Two recent studies published in Biological Psychiatry by Elsevier utilize innovative technological approaches to probe into schizophrenia using models simulating early human brain development.

Utilization of Brain Organoids in Schizophrenia Research

The premier study employed an unconventional methodology, using three-dimensional brain organoids known to mimic fetal brain development. Headed by lead author Ibrahim A. Akkouh, Ph.D., and senior author Srdjan Djurovic, Ph.D., both affiliated with Oslo University Hospital, the team generated induced pluripotent stem cells (iPSCs) from skin cells collected from 14 schizophrenia patients and 14 healthy control subjects. These iPSCs were then manipulated to evolve into brain-like cortical spheroids.

Significant disparities were observed in the expression of numerous genes between organoids cultivated from patients and those from controls, corroborating the complex genetic influences on schizophrenia. Notably, genes related to neuronal axons were prominently implicated.

Dr. Akkouh stated, “We found that ongoing axonal dysregulation serves as an early risk factor for the disorder.”

The research team monitored organoid maturation at multiple junctures, thereby confirming the enduring nature of these disturbances throughout development.

Dr. Akkouh elaborated, “Our study furnishes unprecedented and previously unattainable insights into the molecular underpinnings of schizophrenia during initial brain growth.”

Examination of the CYFIP1 Gene’s Role

The subsequent study, led by Roy H. Perlis, Ph.D., at Harvard Medical School, honed in on a specific genetic risk locus for schizophrenia. The locus, 15q11.2, has a penetrance rate exceeding 10% and doubles the risk of developing the condition. The CYFIP1 gene within this region has been connected to neuronal synaptic function and is implicated in a range of neurodevelopmental disorders, including schizophrenia and autism.

The gene is highly expressed in microglial cells, the innate immune cells of the brain, but its precise function in these cells remains unclear. The study employed CRISPR technology to eliminate functional CYFIP1 from microglial-like cells derived from healthy volunteers.

Dr. Perlis noted, “Our findings propose that aberrations in CYFIP1 functionality could adversely impact key microglial processes, such as synaptic pruning and neuronal maintenance, thereby contributing to neurodevelopmental and psychiatric disorders, including schizophrenia and autism.”

Conclusive Observations

John Krystal, MD, Editor of Biological Psychiatry, remarked, “These studies shed light on two significant themes: the accelerated elimination of glutamatergic synapses during development and disruptions in the signaling properties of these synapses, both of which could adversely affect neural circuit function and are key to the emergence of symptoms and cognitive deficits seen in schizophrenia.”

Dr. Perlis further stated, “Our results underscore the need to extend our focus beyond neurons when analyzing risk genes. Identifying risk loci is merely the initial step; understanding the cellular context and functional implications of these genes is crucial for the development of effective treatments.”

References:

• “Longitudinal Transcriptomic Analysis of Human Cortical Spheroids Identifies Axonal Dysregulation in the Prenatal Brain as a Mediator of Genetic Risk for Schizophrenia” by Ibrahim A. Akkouh et al., published on September 3, 2023, in Biological Psychiatry. DOI: 10.1016/j.biopsych.2023.08.017
• “Loss of Function in the Neurodevelopmental Disease and Schizophrenia-Associated Gene CYFIP1 in Human Microglia-like Cells Supports a Functional Role in Synaptic Engulfment” by Steven D. Sheridan et al., published on August 11, 2023, in Biological Psychiatry. DOI: 10.1016/j.biopsych.2023.07.022

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More about Schizophrenia Research

• Biological Psychiatry Journal
• Study 1: “Longitudinal Transcriptomic Analysis of Human Cortical Spheroids Identifies Axonal Dysregulation in the Prenatal Brain as a Mediator of Genetic Risk for Schizophrenia”
• Study 2: “Loss of Function in the Neurodevelopmental Disease and Schizophrenia-Associated Gene CYFIP1 in Human Microglia-like Cells Supports a Functional Role in Synaptic Engulfment”