Mutant Screen Reveals the Piccolo’s Control over Depression and Brain-Gonad Crosstalk

Successful sexual reproduction involves a highly complex, genetically encoded interplay between animal physiology and behavior. Here we developed a screen to identify genes essential for rat reproduction based on an unbiased methodology involving mutagenesis via the Sleeping Beauty transposon. As expected, our screen identified genes where reproductive failure was connected to gametogenesis (Btrc, Pan3, Spaca6, Ube2k) and embryogenesis (Alk3, Exoc6b, Slc1a3, Tmx4, Zmynd8). In addition, our screen identified Atg13 (longevity) Dlg1 and Pclo (neuronal disorders), previously not associated with reproduction. Dominant Pclo traits caused epileptiform activity and affected genes supporting GABAergic synaptic transmission (Gabra6, Gabrg3), and animals exhibited a compromised crosstalk between the brain and gonads via disturbed GnRH signaling. Recessive Pclo traits disrupted conspecific recognition required for courtship/mating and were mapped to allelic markers for major depressive disorder (Grm5, Htr2a, Sorcs3, Negr1, Drd2). Thus, Pclo-deficiency in rats link neural networks controlling sexual motivation to Pclo variants that have been associated with human neurological disorders.

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