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Recapitulation and Reversal of Schizophrenia-Related Phenotypes in Setd1a-Deficient Mice
Jun Mukai1, Enrico Cannavò2, Gregg W Crabtree1
1Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Mortimer B. Zuckerman Mind Brain and Behavior Institute Columbia University, New York, NY 10027, USA.
Neuron
|October 14, 2019
Summary
SETD1A gene mutations are linked to schizophrenia. Restoring SETD1A function in adulthood reverses cognitive deficits, and blocking LSD1 offers a potential therapeutic strategy for schizophrenia.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- SETD1A is a key gene associated with schizophrenia risk.
- Loss-of-function mutations in SETD1A lead to cognitive deficits and altered brain function in mice.
Purpose of the Study:
- To investigate the role of SETD1A in neuronal function and cognitive processes.
- To identify molecular mechanisms underlying SETD1A-associated deficits.
- To explore potential therapeutic interventions for SETD1A-related neuropsychiatric disorders.
Main Methods:
- Analysis of Setd1a binding to promoters and enhancers in neurons.
- Transcriptional profiling of Setd1a targets.
- Behavioral testing and morphological analysis in Setd1a-deficient mice.
- Investigating the interaction between Setd1a and LSD1.
Main Results:
- Setd1a binds to both promoters and enhancers, with significant overlap with Mef2 on enhancers.
- Setd1a targets are highly expressed in pyramidal neurons, showing complex transcriptional regulation.
- Evolutionarily conserved Setd1a targets are linked to neuropsychiatric genetic risk.
- Restoring Setd1a expression in adulthood rescues cognitive deficits.
- LSD1 acts as a demethylase counteracting Setd1a; its inhibition rescues behavioral and morphological deficits.
Conclusions:
- SETD1A mutations contribute to schizophrenia susceptibility through effects on neuronal gene expression and function.
- Pharmacological antagonism of LSD1 represents a promising therapeutic avenue for SETD1A-related disorders.
- Understanding SETD1A's regulatory role provides insights into the molecular basis of schizophrenia.
