| First Author | Mazalouskas M | Year | 2015 |
| Journal | Neuropsychopharmacology | Volume | 40 |
| Issue | 8 | Pages | 2015-24 |
| PubMed ID | 25684064 | Mgi Jnum | J:238886 |
| Mgi Id | MGI:5824474 | Doi | 10.1038/npp.2015.51 |
| Citation | Mazalouskas M, et al. (2015) Integrin beta3 Haploinsufficiency Modulates Serotonin Transport and Antidepressant-Sensitive Behavior in Mice. Neuropsychopharmacology 40(8):2015-24 |
| abstractText | Converging lines of evidence have identified genetic interactions between the serotonin transporter (SERT) gene and ITGB3, which encodes the beta3 subunit that forms the alphaIIbbeta3 and alphavbeta3 integrin receptor complexes. Here we examine the consequences of haploinsufficiency in the mouse integrin beta3 subunit gene (Itgb3) on SERT function and selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (SSRI) effectiveness in vivo. Biochemical fractionation studies and immunofluorescent staining of murine brain slices reveal that alphavbeta3 receptors and SERTs are enriched in presynaptic membranes from several brain regions and that alphavbeta3 colocalizes with a subpopulation of SERT-containing synapses in raphe nuclei. Notably, we establish that loss of a single allele of Itgb3 in murine neurons is sufficient to decrease 5-HT uptake by SERT in midbrain synaptosomes. Pharmacological assays to elucidate the alphavbeta3-mediated mechanism of reduced SERT function indicate that decreased integrin beta3 subunit expression scales down the population size of active SERT molecules and, as a consequence, lowers the effective dose of SSRIs. These data are consistent with the existence of a subpopulation of SERTs that are tightly modulated by integrin alphavbeta3 and significantly contribute to global SERT function at 5-HT synapses in the midbrain. Importantly, our screen of a normal human population for single nucleotide polymorphisms in human ITGB3 identified a variant associated with reductions in integrin beta3 expression levels that parallel our mouse findings. Thus, polymorphisms in human ITGB3 may contribute to the differential responsiveness of select patients to SSRIs. |
