Rock2 heterozygosity improves cognitive behavior and endothelial function in a mouse model of 16p11.2 deletion autism syndrome

ABSTRACT Rho-associated coiled-coil containing protein kinase-2 (ROCK2) is a critical player in many cellular processes and has been incriminated in cardiovascular and neurological conditions. Recent evidence has shown that non-selective pharmacological ROCK inhibition ameliorates behavioral alterations in an autism mouse model of 16p11.2 haploinsufficiency. We had also revealed that 16p11.2-deficient mice display cerebrovascular abnormalities, including endothelial dysfunction. To investigate whether genetic blockage of ROCK2 also exerts beneficial effects on cognition and angiogenesis, we generated mice with both 16p11.2 and ROCK2 haploinsufficiency ( 16p11.2 df/+ ;Rock2 +/- ). We find that Rock2 heterozygosity on a 16p11.2 df/+ background rescues recognition memory and slightly reduces repetitive behaviors. Furthermore, brain endothelial cells (ECs) isolated from 16p11.2 df/+ ;Rock2 +/- mice display improved angiogenic capacity compared to ECs from 16p11.2 df/+ littermates. Overall, this study implicates Rock2 gene as a critical modulator in 16p11.2-associated alterations, highlighting its potential as a target for treatment of autism spectrum disorders.