Summary: Chromosome 16p11.2 duplication impacts several different inhibitory neuron types that use GABA in brain areas that are dysfunctional in schizophrenia, including the prefrontal cortex, hippocampus, and amygdala. The chromosome 16p11.2 duplication also resulted in cognitive and social deficits that are symptomatic of schizophrenia.
Source: Lancaster University
A genetic change increases the risk of developing schizophrenia and highlights new opportunities for drug treatment say researchers.
The collaborative research by a team from Lancaster, Glasgow and Strathclyde Universities was funded by the Medical Research Council.
In the human genome, small sections of DNA have been found to be duplicated (copied) or deleted in a small number of people, a phenomenon known as Copy Number Variation. Some of these genetic changes are linked to an increased risk of developing neurodevelopmental disorders, such as schizophrenia and autism, but the disease mechanisms involved remain largely unknown. For example, people with a DNA duplication at chromosome 16p11.2, that results in having extra copies of around 30 different genes, are approximately 15 times more likely to develop schizophrenia than people without the duplication. Why this should be the case is very poorly understood.
For the first time, research reported by the team in the journal Cell Reports, has shown that the 16p11.2 duplication impacts on a number of different inhibitory neuron types, neurons that use the neurotransmitter GABA, in brain areas dysfunctional in schizophrenia. These brain areas include the prefrontal cortex, hippocampus and amygdala. The researchers also show that these GABA neuron changes are accompanied by impaired functional communication between the same brain regions. Importantly, the researchers found that 16p11.2 duplication also results in cognitive and social deficits. These deficits not only parallel those seen in patients with schizophrenia, but are also known to involve the brain regions identified as being dysfunctional as a result of 16p11.2 duplication.
Dr Neil Dawson, the lead researcher from Lancaster University said: “Our data give new insight into how 16p11.2 duplication increases the risk of developing schizophrenia and the mechanisms involved. A key finding is the observation of disrupted connectivity between brain regions that are known to be dysfunctional in schizophrenia. We can now test the ability of drugs to restore these changes as part of ongoing research to develop better treatments for the disorder”.
Professor Judith Pratt, the lead research from Strathclyde University, also highlighted the potential opportunity for drug development given these findings. “The current drug treatment options available for people with schizophrenia are limited, only effective for some patients and often involve severe side effects. Drugs to help patients with their cognitive and social problems are particularly urgently needed, as these symptoms dramatically impact on their quality of life. Our findings highlight the potential of drugs targeting the GABA neurons and provide a range of translational biomarker measures against which we can test the potential therapeutic efficacy of these and other drugs for schizophrenia”.
Professor Brian Morris, the lead researcher from Glasgow University adds: “The finding of disturbed GABA neuron function as a consequence of 16p11.2 duplication is particularly intriguing, given that we know these cell types are dysfunctional in the brains of people with schizophrenia. This suggests that we are now closer to pinpointing the genes that regulate GABA cell function, and hence in the future to a potential approach to 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.
16p11 Duplication Disrupts HippocampalOrbitofrontal-Amygdala Connectivity, Revealing a Neural Circuit Endophenotype for Schizophrenia
Chromosome 16p11.2 duplications dramatically increase risk for schizophrenia, but the mechanisms remain largely unknown. Here, we show that mice with an equivalent genetic mutation (16p11.2 duplication mice) exhibit impaired hippocampal-orbitofrontal and hippocampal-amygdala functional connectivity. Expression of schizophrenia-relevant GABAergic cell markers (parvalbumin and calbindin) is selectively decreased in orbitofrontal cortex, while somatostatin expression is decreased in lateral amygdala. When 16p11.2 duplication mice are tested in cognitive tasks dependent on hippocampal-orbitofrontal connectivity, performance is impaired in an 8-arm maze ‘‘N-back’’ working memory task and in a touchscreen continuous performance task. Consistent with hippocampal-amygdala dysconnectivity, deficits in ethologically relevant social behaviors are also observed. Overall, the cellular/molecular, brain network, and behavioral alterations markedly mirror those observed in schizophrenia patients. Moreover, the data suggest that 16p11.2 duplications selectively impact hippocampal-amygdaloid-orbitofrontal circuitry, supporting emerging ideas that dysfunction in this network is a core element of schizophrenia and defining a neural circuit endophenotype for the disease.