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The mammalian vomeronasal organ (VNO) has emerged as an excellent model to investigate the signaling mechanisms, mode of activation, biological function, and molecular evolution of transient receptor potential (TRP) channels in real neurons and real physiological systems. TRPC2, a member of the canonical TRPC subfamily, is highly localized to the dendritic tip of vomeronasal sensory neurons. Targeted deletion of the TRPC2 gene has established that TRPC2 plays a fundamental role in the detection of pheromonal signals by the VNO. TRPC2-deficient mice exhibit striking behavioral defects in the regulation of sexual and social behaviors.
TRPC2-deficient mice have afforded an excellent opportunity to define the role of the VNO in the generation of innate sexual and social behaviors in mice. This work has shown that deletion of only a single gene from the genome can lead to striking defects in complex social behaviors (Leypold et al. 2002; Stowers et al. 2002). Two key results have emerged from these investigations thus far. First, TRPC2 is essential for pheromone-evoked male–male aggression. In a resident-intruder assay, which tests for intermale aggression, resident TRPC2–/– males fail to initiate attack behavior, although they are physically and neurologically capable of displaying aggressive interactions (Leypold et al. 2002; Stowers et al. 2002). Interestingly, presumably as a result of the lack of an aggressive response, TRPC2–/– males fail also to establish dominance hierarchies and instead display urine marking behavior typical of subordinate males (Leypold et al. 2002). Aggressive behavior is also severely attenuated in lactating female TRPC2–/– mice that are confronted with a male intruder, indicating that signals transduced by the VNO initiate aggressive behavior in both males and females (Leypold et al. 2002).
Second, a striking defect is also seen in the sexual behavior of TRPC2–/– males. Although TRPC2–/– males mate normally with females, they display increased sexual behavior towards other males, i.e., mounting other males at a much higher rate (Leypold et al. 2002; Stowers et al. 2002). This behavior had not been observed previously in animals in which the VNO was surgically ablated. This unexpected result has been interpreted as evidence that TRPC2-mediated signaling may be essential for gender discrimination (Stowers et al, 2002). One possible model consistent with these data is that mounting is an innate behavior that is inhibited by male pheromones acting through the VNO. TRPC2–/– males, therefore, persist in mounting other males. Because of the absence of major defects in male–female sexual behavior in TRPC2–/– mice, pheromones or other sensory cues essential for mating may not be detected by the VNO, but rather by other sensory systems such as the main olfactory epithelium.
Hence, it is now clear that TRPC2 is essential for the detection of male-specific cues in the VNO that, in turn, regulate the expression of complex behavioral repertoires including aggressive and sexual interactions.