Derepression of transposable elements in the mouse prefrontal cortex disrupts social behavior

The neurobiological origins of social behaviors are poorly understood. Previous studies have linked the function of a single Krüppel-associated box zinc finger protein (KZFP), ZFP189, in the mouse prefrontal cortex (PFC), with the regulation of transposable elements (TEs), immune genes, and social behaviors. Here, we expand the scope of inquiry to explore the relationship between collective PFC KZFP function and social behaviors by altering the function of the cognate KZFP interacting protein TRIM28 within the PFC of male and female mice. We reprogrammed natural TRIM28^WT by replacing the endogenous, transcriptionally repressive domain with a synthetic, enhanced transcriptional activation domain VP64-p65-Rta (TRIM28^VPR) or by excising the transcriptional regulatory domain (TRIM28^NFD). Upon intra-PFC viral-mediated delivery of TRIM28 variants, we observed that inversion of TRIM28 transcriptional control via HSV-TRIM28^VPR selectively produced deficits in social behaviors, without affecting nonsocial behaviors. RNA sequencing of manipulated PFC revealed that HSV-TRIM28^VPR drove transcriptional escape of all classes of TEs, particularly those located within intronic and enhancer regions proximal to downregulated immune genes. HSV-TRIM28^VPR-mediated social deficits were reversible by intra-PFC repletion of interferon cytokines. These data point to PFC KZFP-TRIM28 interactions as necessary to stabilize genomic TEs to enable <i>cis</i>-regulation of key immune gene expression, which enhances organismal capacity for complex, prosocial behaviors.