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Reversal of Schizophrenia Memory Deficits

  • Mutations in the gene SETD1A in rodents were recently found to be linked to spatial working memory deficits, dysconnectivity in the synaptic dynamics of cortical neurons, and targets enhancers, which regulate genes involved in synaptic structure and function at early life. These gene mutations were found to exist in both mice and humans.

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Neuron

Recapitulation and reversal of schizophrenia-related phenotypes in SETD1A-deficient mice
Mukai et al., 2019
Neuron, 2019; DOI: https://doi.org/10.1016/j.neuron.2019.09.014
“Schizophrenia is thought to be a neurodevelopmental disorder that begins years before it can actually be diagnosed, making the disease’s underlying aspects extremely difficult to understand and treat.”

Reversal of Schizophrenia-Related Cognitive Impairment in Mice

Schizophrenia is a neuropsychiatric disorder that presents a variety of symptoms classified as positive, negative and cognitive. Cognitive impairment is a core feature of the disorder and may include difficulty in processing information or decision making, trouble focusing and impairment of the short, “working” memory.1 These symptoms arise early in childhood and for that reason early interventions focus on tackling them to achieve treatment before progress to psychosis.1 However, at this early stage schizophrenia cannot yet be diagnosed.1 Therefore, the real challenge is to understand and treat schizophrenia at later stages in adult life.
 
Studies have revealed a correlation between certain rare mutations and development of schizophrenia.2,3 Mutations in the gene SETD1A, producing a histone methyltransferase, have been linked to increased risk of developing the disorder,4 but it wasn’t until very recently that scientists utilised this knowledge to model the disease and explore its molecular mechanisms and potential therapeutic opportunities. In a 2019 study, Mukai et al. at Columbia University used adult mice carrying the SETD1A mutation to uncover the potential role of the SETD1A factor in the neural networks that take part in memory.5 Their approach and key findings are presented below:

Behavioural assays indicated that the loss of function of SETD1A in adult mice causes spatial working memory deficits, that recapitulate the cognitive phenotype of psychotic disorders.6

Further analysis of the cortex and field recordings showed alterations in the way cortical neurons branch and common dysconnectivity in their synaptic dynamics.5 Moreover, a role for SETD1A in early neurogenesis in the cortex was revealed.5

Gene expression analysis suggested that SETD1A targets mostly enhancers, the regions of the DNA that can be bound by proteins to increase the likelihood that transcription of a particular gene will occur.5 These targets are primarily found in the pyramidal neurons of the cortex and mainly regulate genes involved in synaptic structure and function at early life.5

Genome-wide analysis revealed that the SETD1A gene targets are evolutionary conserved between mice and humans.5 Further gene ontology data indicated that these genes are highly expressed in schizophrenia and therefore strongly associated with neuropsychiatric genetic risk burden.5


How Can These Findings be Translated in a Clinical Setting?

Mukai et al. attempted pharmacological interventions using known inhibitors of the downstream demethylation processes in the Setd1a pathway.5 Specifically, they argued that the demethylase LSD1 is a promising antagonist of Setd1a that counteracts the negative effects of Setd1a deficiency.5 Among the findings, a full rescue of the behavioural abnormalities and axonal branching deficits were observed.5 These results may open new avenues in developing effective therapeutics in schizophrenia. Several LSD1 inhibitors are in early-stage clinical trials for cancer.7 These inhibitors could potentially be repurposed for schizophrenia treatment.7 More studies are required to fully understand the role of SETD1A in humans. This will allow researchers to investigate how to best alleviate the debilitating cognitive symptoms many people encounter throughout their lives.

References

  1. Hashimoto K. Recent Advances in the Early Intervention in Schizophrenia: Future Direction from Preclinical Findings. Curr Psychiatry Rep. 2019. doi:10.1007/s11920-019-1063-7
  2. Flint J. Rare genetic variants and schizophrenia. Nat Neurosci. 2016. doi:10.1038/nn.4271
  3. Fromer M, Pocklington AJ, Kavanagh DH, et al. De novo mutations in schizophrenia implicate synaptic networks. Nature. 2014. doi:10.1038/nature12929
  4. Singh T, Kurki MI, Curtis D, et al. Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders. Nat Neurosci. 2016. doi:10.1038/nn.4267
  5. Mukai J, Cannavò E, Crabtree GW, et al. Recapitulation and reversal of schizophrenia-related phenotypes in Setd1a-deficient mice. Neuron. 2019. doi:10.1101/529701
  6. Arguello PA, Gogos JA. Genetic and cognitive windows into circuit mechanisms of psychiatric disease. Trends Neurosci. 2012. doi:10.1016/j.tins.2011.11.007
  7. https://www.genengnews.com/news/schizophrenia-memory-deficits-reversed-in-adult-mice/ [accessed on 18th October 2019]
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