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PHF8 is a histone demethylase with specificity for repressive modifications. While mutations of  PHF8  have been associated with cognitive defects and cleft lip/palate, its role in mammalian development and physiology remains unexplored. Here, we have generated a  Phf8  knockout allele in mice to examine the consequences of  Phf8  loss for development and behaviour.  Phf8  deficient mice neither display obvious developmental defects nor signs of cognitive impairment. However, we report a striking resiliency to stress-induced anxiety- and depression-like behaviour on loss of  Phf8 . We further observe misregulation of serotonin signalling within the prefrontal cortex of  Phf8  deficient mice and identify the serotonin receptors  Htr1a  and  Htr2a  as direct targets of PHF8. Our results clarify the functional role of  Phf8  in mammalian development and behaviour and establish a direct link between  Phf8  expression and serotonin signalling, identifying this histone demethylase as a potential target for the treatment of anxiety and depression.

Phf8 loss confers resistance to depression-like and anxiety-like behaviors in mice