Collagen VI deficiency causes behavioral abnormalities and cortical dopaminergic dysfunction

Mutations of genes coding for Collagen VI (COL6) cause muscle diseases, including Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM). Although more recently COL6 genetic variants were linked to brain pathologies, the impact of COL6 deficiency in brain function is still largely unknown. Here, a thorough behavioral characterization of COL6 null (Col6a1-/-) mice unexpectedly revealed that COL6 deficiency leads to a significant impairment in sensorimotor gating and memory/attention functions. In keeping with these behavioral abnormalities, Col6a1-/- mice displayed alterations in dopaminergic signalling, primarily in the prefrontal cortex (PFC). In vitro co-culture of SH-SY5Y neural cells with primary meningeal fibroblasts from wild-type and Col6a1-/- mice confirmed a direct link between COL6 ablation and defective dopaminergic activity, through a mechanism involving the inability of meningeal cells to sustain dopaminergic differentiation. Finally, patients affected by COL6-related myopathies were evaluated with an ad hoc neuropsychological protocol, revealing distinctive defects in attentional control abilities. Altogether, these findings point at a novel role for COL6 in the proper maintenance of dopamine circuitry function and its related neurobehavioral features in both mice and humans.