[Abstract] 

 Obsessive Compulsive Disorder (OCD) displays a substantial heritable component but few specific molecular genetic risk factors have been identified. Knockout mice lacking Slitrk5 expression display an OCD-like phenotype involving pathologic grooming that is responsive to serotonin reuptake inhibitors and corticostriatal dysfunction. To examine whether Slitrk5 function contribute to the genetic risk for OCD, we re-sequenced the complete protein coding sequence of SLITRK5 in a population sample of human OCD subjects. Direct functional testing of identified OCD-specific rare non-synonymous mutations in Slitrk5 found that all mutations showed impaired synaptogenic activity as well as diminished binding to PTPd, a trans-synaptic binding partner of Slitrks. These results demonstrate that rare mutations in SLITRK5 contribute to the genetic risk for OCD in human populations. We previously reported that Slitrk5 modulates BDNF-dependent biological responses through direct interaction with TrkB receptors. Under basal conditions, Slitrk5 interacts primarily with PTPd; however, upon BDNF stimulation, Slitrk5 shifts to cis-interactions with TrkB. Interestingly, genetic facilitation of TrkB signaling rescued repetitive phenotype of Slitrk5 KO mice while deletion of BDNF expression in OCD circuit induced increase in grooming behavior. The networks of genes implicated in OCD remain obscure, however, these findings suggest that BDNF-dependent regulation of TrkB, Slitrk5, and PTPd interactions at the synapse may mediate proper functioning of key corticostriatal circuits implicated in OCD.