Impairment Of Neural Plasticity And Adaptive Representations By Genetic Risk Factors For Schizophrenia

Lead Research Organisation: University of Bristol
Department Name: Physiology and Pharmacology


Schizophrenia is a severe neurodevelopmental disorder, most commonly diagnosed in late teens/early 20s, that affects ~1% of the population. The disorder places a major burden on sufferers, carers and health services evidenced by high suicide rates in sufferers (~7%) and consuming ~30% of NHS spending on adult mental health. In England alone, the economic cost of schizophrenia is estimated at £12 billion/year. Psychotherapy is not an effective treatment on its own and although there are some effective medications, those that are licenced are often poorly tolerated. Therefore, there is a large unmet need to identify new treatments.

To develop new treatments, we need to understand the underlying biological causes of schizophrenia. A powerful guide comes from analysis of genetic mutations in large studies of people with schizophrenia, the most recent of which, published this year, highlight 10 individual genes whose disruption confers a high risk of developing the disorder. Of these genes, 4 are directly associated with synaptic function and the ability for neuronal connections to adapt providing a strong guide to the underlying biological causes. However, it is not clear whether these genetic mutations cause similar biological disruptions. This is important for determining what degree of personalisation is required for therapeutic strategies.

Calcium signals in the branches of neurons drive synaptic adaptations and are incredibly sensitive to small perturbations in neuronal function. Our recent data suggest that disruption to individual genes associated with risk for schizophrenia cause a common disruption to these calcium signals. Since synaptic adaptations are fundamental to cognitive processes such as memory, we further propose that this leads to cognitive impairment.

Our interdisciplinary programme provides a holistic approach to test this hypothesis using high-resolution calcium imaging of neurons in intact brain tissue that carry specific genetic mutations replicating those found in schizophrenia. We will introduce these mutations into mice, and into human neurons removed from patients undergoing brain surgery. We will link disruptions to neuronal calcium signals through to behaviour, by assessing cognitive function in mice. Based on our findings, we will also explore potential drug targets to rescue neuronal calcium signalling. Using tissue taken from mice and humans at different developmental stages we will also discover if these biological disruptions occur in advance of the emergence of psychosis and diagnosis, most commonly in late teens/early adulthood, which might lead to the development of novel early biological signs for schizophrenia.

Overall, this programme aims to develop a platform to understand underlying biological disruptions to cognitive processes that occur in schizophrenia, and explore mechanisms to reverse them. In future we can test other genetic mutations associated with schizophrenia, but we can also explore whether other psychiatric disorders with strong elements of genetic risk such as autism also exhibit disrupted neuronal calcium signalling. Indeed, many genes associated with schizophrenia are also associated with autism and it will be important to find out why specific mutations lead to one disorder or another.

Technical Summary

Genetic factors confer the majority of risk for schizophrenia (SZ) and provide powerful insight into the underlying biological causes. Indeed, the most recent high-powered genomic association studies from the SCHEMA Consortium identified 10 individual genes that are ultra-high penetrance risk factors for SZ of which 4 are directly associated with synaptic Ca2+ regulation and plasticity. There is also strong evidence for the involvement of the hippocampus in the development of schizophrenia, and disruption of hippocampal plasticity likely plays a central role in the cognitive impairments seen in SZ. Thus, evidence suggests that disruption to core features of synapses and synaptic plasticity in the hippocampus represent fundamental biological phenotypes contributing to cognitive impairments in SZ.

Our recent studies have highlighted shared sensitivities of dendritic Ca2+ signalling and synaptic plasticity to disruptions in individual genes associated with SZ. These results suggest dendritic Ca2+ signalling as a potential therapeutic target to rescue behavioural phenotypes. We propose to investigate how high penetrance genetic risk factors, identified by the SCHEMA analyses, disrupt neural plasticity processes and resulting flexible representations and at what stage of development they become apparent. We hypothesise convergence between risk factors on dendritic Ca2+ signalling, but the degree of divergence is also important for developing personalised therapeutic strategies. We will integrate ex vivo and in vivo approaches in rodents with disruptions to specific genes to link mechanisms from synapses through to adaptive behaviour and test potential targets to rescue cognitive impairments. Crucially, we will also test mechanisms and therapeutic potential for targets in living human neuronal networks. Our overall aim is to develop a platform to understand underlying biological disruptions to cognitive processes that occur in SZ and explore mechanisms to reverse them.


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