Btbd3 expression regulates compulsive-like and exploratory behaviors in mice

Abstract

AbstractBTB/POZ domain-containing 3 (BTBD3) was identified as a potential risk gene in the first genome-wide association study of obsessive-compulsive disorder (OCD). BTBD3 is a putative transcription factor implicated in dendritic pruning in developing primary sensory cortices. We assessed whether BTBD3 also regulates neural circuit formation within limbic cortico-striato-thalamo-cortical circuits and behaviors related to OCD in mice. Behavioral phenotypes associated with OCD that are measurable in animals include compulsive-like behaviors and reduced exploration. We testedBtbd3wild-type, heterozygous, and knockout mice for compulsive-like behaviors including cage-mate barbering, excessive wheel-running, repetitive locomotor patterns, and reduced goal-directed behavior in the probabilistic learning task (PLT), and for exploratory behavior in the open field, digging, and marble-burying tests.Btbd3heterozygous and knockout mice showed excessive barbering, wheel-running, impaired goal-directed behavior in the PLT, and reduced exploration. Further, chronic treatment with fluoxetine, but not desipramine, reduced barbering inBtbd3wild-type and heterozygous, but not knockout mice. In contrast,Btbd3expression did not alter anxiety-like, depression-like, or sensorimotor behaviors. We also quantified dendritic morphology within anterior cingulate cortex, mediodorsal thalamus, and hippocampus, regions of highBtbd3expression. Surprisingly,Btbd3knockout mice only showed modest increases in spine density in the anterior cingulate, while dendritic morphology was unaltered elsewhere. Finally, we virally knocked downBtbd3expression in whole, or just dorsal, hippocampus during neonatal development and assessed behavior during adulthood. Whole, but not dorsal, hippocampalBtbd3knockdown recapitulatedBtbd3knockout phenotypes. Our findings reveal that hippocampalBtbd3expression selectively modulates compulsive-like and exploratory behavior.