In a study recently published online in Molecular Psychiatry, researchers from numerous US universities elucidated the role of DIX domain containing-1 (DIXDC1), an intracellular protein of the Wnt/β-catenin signaling pathway, in the pathogenesis of mental illness.
Previous genomics studies have implicated the Wnt/β-catenin signaling pathway as one that may confer vulnerability to psychiatric illness, and DIXDC1 may have a relevant role as suggested by higher levels of anxiety and depression in mice lacking the protein. DIXDC1 interacts with the DISC1 (disrupted in schizophrenia 1) gene, which has also been linked with genetic risk of various psychiatric disorders.
“Compared with some core Wnt/β-catenin pathway components, DIXDC1 has a relatively restricted tissue distribution including in the late developmental and postnatal central nervous system… suggesting that it might have specialized roles in neurons and that its functional sequence variants might manifest as behavioral syndromes in the human population,” wrote the authors of the current study.
To investigate this possibility, they conducted various analyses using a Dixdc1 knockout (Dixdc1KO) mouse model and human genetic data pertaining to bipolar disorder, schizophrenia, and autism spectrum disorder. Their findings revealed the following observations:
Compared to wild-type mice, the Dixdc1KO mice demonstrated behaviors suggestive of depression, anxiety, and impaired social behavior: In various tests, they spent more time immobile and spent less time in the center of an open field, showed more avoidant behavior, and spent less time in social interactions.
Dixdc1KO mice showed reduced density of dendritic spines and glutamatergic synapses in the pyramidal neurons. Wnt/β-catenin signal transduction was impaired in the neurons of Dixdc1KO mice, and evidence suggests that either hyperactivity or hypoactivity of this pathway during neural differentiation could lead to the observed reductions in density of the dendritic spines and glutamatergic synapses.
Injecting the Dixdc1KO mice with either lithium chloride, which activates the Wnt/β-catenin pathway via direct inhibition of glycogen synthase kinase-3 (GSK3), or with a GSK3 inhibitor corrected the behavioral abnormalities. These injections also corrected the density of dendritic spines and glutamatergic synapses in pyramidal neurons of the Dixdc1KO mice, supporting the researchers’ hypothesis that such deficits correspond with the observed behavioral abnormalities.
Compared to nonpsychiatric controls, data sets of psychiatric patients with autism spectrum disorder, bipolar disorder, and schizophrenia demonstrated a higher burden of rare sequence-disrupting single nucleotide variants (SNV) in 2 major DIXDC1 isoforms. Rare SNVs that hyperactivate the Wnt/β-catenin pathway caused deficits in dendritic spine density and maturity, as well as glutamatergic synapse density.
Taken together, these findings “support that altered Wnt/β-catenin signaling generates neurodevelopmental and behavioral phenotypes in Dixdc1KO mice and contributes to neurodisruptive effects of rare DIXDC1 sequence variants in human psychiatric patients,” according to the paper. The results also implicate abnormal spine and glutamatergic density in the development of psychiatric disorders, and the “correlation between GSK3, behavior, dendritic spine and glutamatergic synapse phenotypes supports the notion that spines and glutamatergic synapses are critical biological substrates underlying lithium-responsive psychiatric conditions,” the authors stated.
Martin PM, Stanley RE, Ross AP, et al. DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/β-catenin signaling. Mol Psychiatry. 2016; doi: 10.1038/mp.2016.184.