SAT-LB070 Tachykinins Are Essential for the Induction of the Preovulatory LH Surge in Mice

Tachykinins (TACs) result from the differential processing of two genes in rodents, Tac1 (encoding substance P (SP) and neurokinin A (NKA)) and Tac2 (encoding NKB). TACs exert their effects in the hypothalamus by acting on different G protein-coupled receptors (GPCRs): NK1R, the receptor of SP, NK2R, the receptor of NKA, and NK3R, the receptor of NKB. We and others have documented a stimulatory role for all these tachykinins in the release of GnRH in the presence of physiological circulating levels of sex steroids. Important cross-reactivity between the TAC ligand-receptor systems has been documented and suggested as a possible cause for the reversal of hypogonadal NKB-signaling deficient patients. In order to test the possible redundancy in the TAC systems, we generated a mouse model of congenital removal of all TACs ( Tac1 KO/ Tac2 KO, aka TACKO). This model revealed a sexually dimorphic effect of TACs on puberty onset and fertility. TACKO male mice (n= 14) displayed delayed puberty onset compared with wildtype (WT) littermates, resembling Tac1 KO and Tac2 KO mice separately, but retained normal fertility. By contrast, TACKO females presented a slight delay in the timing of vaginal opening (VO) -a marker of puberty onset—, compared to controls, but none of the females (n=10) presented signs of first estrus within 30 days after VO, indicating a failure to undergo complete sexual maturation. This was supported by a profound reproductive impairment, as only 20% of the TACKO females that were mated with fertile WT males for 8 weeks delivered pups (and these litters presented a significantly reduced number of pups and significantly larger parturition latency than controls). To test the ability of TACKO females to mount a normal LH surge, a similar cohort of TACKO females (n = 5) was subjected to an LH surge inducing protocol, which evidenced the absence of a detectable preovulatory surge in KO mice. Overall, these data suggest a novel role for TACs as essential players in the induction of the preovulatory LH surge in females, through a redundant mechanism that is only evident in the absence of all TACs, but not in the absence of Tac1 or Tac2 , separately. These data further suggest that while TACs participate in the timing of puberty onset in both sexes, they are dispensable for the tonic (pulsatile) release of GnRH/LH as evidenced by the normal fertile phenotype of male TACKO mice. Because preoptic area Kiss1 neurons do not coexpress TACs, these findings str