Summary: Duplication of chromosome region 16p11.2 alters multiple types of GABA-producing inhibitory neurons in brain regions implicated in schizophrenia — including the prefrontal cortex, hippocampus and amygdala — and leads to cognitive and social impairments that resemble symptoms of the disorder.
Source: Lancaster University
Genetic change linked to higher schizophrenia risk points to new drug targets
Researchers from Lancaster, Glasgow and Strathclyde Universities, supported by the Medical Research Council, report new insights into how a specific genetic alteration increases schizophrenia risk and identify opportunities for therapeutic development. The work focuses on copy number variation (CNV) at chromosome 16p11.2, a duplication that gives extra copies of roughly 30 genes and is associated with an approximately 15-fold increased risk of schizophrenia.
Copy number variation—small segments of DNA that are deleted or duplicated in some individuals—has been linked to a range of neurodevelopmental disorders, including schizophrenia and autism. Until now, the cellular and circuit-level mechanisms that connect particular CNVs to psychiatric illness have remained unclear. This study, published in Cell Reports, examines how the 16p11.2 duplication affects inhibitory GABAergic neurons, neural circuitry, and behavior in an animal model carrying the equivalent genetic change.
For the first time, the team demonstrates that the 16p11.2 duplication selectively disrupts several subtypes of inhibitory (GABA) neurons in brain regions known to be dysfunctional in schizophrenia: the prefrontal cortex (including orbitofrontal regions), hippocampus, and lateral amygdala. These alterations in GABAergic cell markers — including reductions in parvalbumin, calbindin and somatostatin expression in region-specific patterns — are accompanied by impaired functional connectivity between hippocampus, orbitofrontal cortex and amygdala. The combination of cellular, network, and behavioral changes defines a neural circuit endophenotype relevant to schizophrenia.
Behaviorally, mice carrying the 16p11.2 duplication display deficits in cognitive and social domains that map onto the affected circuitry. The animals show impaired performance on tasks that require hippocampal–orbitofrontal communication, including an 8-arm “N-back” working memory task and a touchscreen continuous performance test. Consistent with disrupted hippocampal–amygdala connectivity, these mice also exhibit alterations in ethologically relevant social behaviors. Together, the findings mirror many cellular and network abnormalities observed in people with schizophrenia and strengthen the link between 16p11.2 duplication and the disorder’s cognitive and social symptoms.
Dr Neil Dawson (Lancaster University), lead author on the study, emphasized the translational value of these findings: “Our data reveal how the 16p11.2 duplication can increase schizophrenia risk by disrupting connectivity between key brain regions. These measurable changes give us concrete targets and biomarkers for testing drugs that might restore normal network function.”
Professor Judith Pratt (Strathclyde University) highlighted the urgent need for improved treatments: “Current medications for schizophrenia often fail to treat cognitive and social impairments and can cause serious side effects. Our results suggest that drugs targeting GABAergic neurons and the circuits they regulate could address those unmet needs. The biomarkers we describe provide a way to evaluate potential therapies in preclinical studies and, ultimately, clinical trials.”
Professor Brian Morris (Glasgow University) added that identifying disturbed GABA cell function as a consequence of 16p11.2 duplication brings researchers closer to pinpointing the genes that control inhibitory neuron behavior: “This opens a path toward strategies that could normalize GABAergic function and help people with schizophrenia.”
About this schizophrenia research article
Source:
Lancaster University
Media Contacts:
Gillian Whitworth – Lancaster University
Image Source:
The image is credited to Lancaster University.
Original Research (Open access):
“16p11 Duplication Disrupts Hippocampal–Orbitofrontal–Amygdala Connectivity, Revealing a Neural Circuit Endophenotype for Schizophrenia.” by Greg C. Bristow, David M. Thomson, Rebecca L. Openshaw, Emma J. Mitchell, Judith A. Pratt, Neil Dawson, Brian J. Morris. Cell Reports. DOI: 10.1016/j.celrep.2020.107536.
Abstract
Chromosome 16p11.2 duplications dramatically increase risk for schizophrenia, but the mechanisms remain largely unknown. Mice modeling the 16p11.2 duplication show impaired hippocampal–orbitofrontal and hippocampal–amygdala functional connectivity. Expression of schizophrenia-relevant GABAergic markers (parvalbumin and calbindin) is selectively decreased in orbitofrontal cortex, while somatostatin expression is reduced in lateral amygdala. These mice perform poorly on hippocampal–orbitofrontal dependent cognitive tasks, including an 8-arm “N-back” working memory task and a touchscreen continuous performance task, and they exhibit deficits in social behaviors consistent with hippocampal–amygdala dysconnectivity. The combined cellular, network, and behavioral alterations parallel observations in schizophrenia patients and indicate that 16p11.2 duplication selectively impacts hippocampal–amygdaloid–orbitofrontal circuitry, defining a neural circuit endophenotype for the disorder.
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