Disproportionate neuroanatomical effects of DCC haploinsufficiency in adolescence compared with adulthood: links to dopamine, connectivity, covariance, and gene expression brain maps in mice

Critical adolescent neural refinement is controlled by the DCC (deleted in colorectal cancer) protein, a receptor for the netrin-1 guidance cue. We sought to describe the effects of reduced on neuroanatomy in the adolescent and adult mouse brain. We examined neuronal connectivity, structural covariance, and molecular processes in a -haploinsufficient mouse model, compared with wild-type mice, using new, custom analytical tools designed to leverage publicly available databases from the Allen Institute. We included 11 -haploinsufficient mice and 16 wild-type littermates. Neuroanatomical effects of haploinsufficiency were more severe in adolescence than adulthood and were largely restricted to the mesocorticolimbic dopamine system. The latter finding was consistent whether we identified the regions of the mesocorticolimbic dopamine system a priori or used connectivity data from the Allen Brain Atlas to determine de novo where these dopamine axons terminated. Covariance analyses found that haploinsufficiency disrupted the coordinated development of the brain regions that make up the mesocorticolimbic dopamine system. Gene expression maps pointed to molecular processes involving the expression of , (encoding DCC's co-receptor), and (encoding its ligand, netrin-1) as underlying our structural findings. Our study involved a single sex (males) at only 2 ages. The neuroanatomical phenotype of haploinsufficiency described in mice parallels that observed in -haploinsufficient humans. It is critical to understand the haploinsufficient mouse as a clinically relevant model system.