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

Abstract

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 histone demethylase deficiency causes cognitive impairments through the mTOR pathway

“…Although both our study and those in ref. 35 found the Phf8 -deficient mice showed hyperactivity in open-field test, our Phf8 KO mice displayed a significant intellectual disability in water maze, Barnes maze and passive avoidance performance as well as LTP deficit. The difference of behavior phenotype in Phf8 -deficient mice in two studies may be due to the genetic factors.…”

“…A recent paper reported that a different strain of Phf8 -deficient mice showed resilience to stress induced anxiety- and depression-related behavior and no intellectual disability 35 . Although both our study and those in ref.…”

“…Our testing mice were at least the fifth-generation progeny of a backcross into C57BL/6 J mice while the KO mice in ref. 35 were maintained on a 129/B6 background. In addition, subtle difference in the methods for behavioral testing may contribute to the difference in phenotype.…”

“…Our study used a classical 5-min training protocol for contextual fear conditioning to evaluate fear memory, and measured the freezing level for 5 min 24 h later. The other study 35 used different training regimen and testing protocol which may have resulted in memory traces of different strength.…”

Histone Lysine Methylation and Neurodevelopmental Disorders

“…Furthermore, injection of zebrafish PHF8 morpholino caused brain and craniofacial development defects [ 96 ], thus suggested a critical role of histone methylation dynamics regulated by PHF8 in MRXSSD. However, surprisingly, a recent study showed that Phf8 -deficient mice had no obvious developmental defects and cognitive impairment, while Phf8 -deficient primary cells had reduced the proliferative potential [ 98 ]. The results in mice indicated that MRXSSD is not simply caused by a single PFH8 mutation, but rather by its combination with other genetic or environmental factors at the same time.…”