Division of Neurogenetics / Iwasato Group

Serotonergic axons extend diffuse projections throughout various brain areas, and serotonergic system disruption causes neuropsychiatric diseases. Loss of the cytoplasmic region of protocadherin-α (Pcdh-α) family proteins, products of the diverse clustered Pcdh genes, causes unbalanced distributions (densification and sparsification) of serotonergic axons in various target regions. However, which Pcdh-α member(s) are responsible for the phenotype is unknown. Here we demonstrated that Pcdh-αC2 (αC2), a Pcdh-α isoform, was highly expressed in serotonergic neurons, and was required for normal diffusion in single-axon-level analyses of serotonergic axons. The loss of αC2 from serotonergic neurons, but not from their target brain regions, led to unbalanced distributions of serotonergic axons. Our results suggest that αC2 expressed in serotonergic neurons is required for serotonergic axon diffusion in various brain areas. The αC2 extracellular domain displays homophilic binding activity, suggesting that its homophilic interaction between serotonergic axons regulates axonal density via αC2’s cytoplasmic domain.

Figure. Serotonergic axons in the olfactory bulb. Wildtype mice (left) show almost uniform distributions in serotonergic axons (magenta) in all layers. In contrast, protocadherin-α C2 deficient mice (right) exhibit unbalanced serotonergic-axon distributions (densification in granule cell layer and sparsification in the other layers). In the granule cell layer (box), fasciculating serotonergic axons are observed.

Source: Scientific Reports 7 Article number: 15908(2017)
DOI: 10.1038/s41598-017-16120-y