Neuroplastin Expression in Male Mice Is Essential for Fertility, Mating, and Adult Testosterone Levels

Male reproduction depends on hormonally driven behaviors and numerous genes for testis development and spermatogenesis. Neuroplastin-deficient (Nptn^-/-) male mice cannot sire offspring. By immunohistochemistry, we characterized neuroplastin expression in the testis. Breeding, mating behavior, hormonal regulation, testicular development, and spermatogenesis were analyzed in cell-type specific neuroplastin mutant mice. Leydig, Sertoli, peritubular myoid, and germ cells express Np, but spermatogenesis and sperm number are not affected in Nptn^-/- males. Neuroplastin lack from CNS neurons or restricted to spermatogonia or Sertoli cells permitted reproduction. Normal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) blood levels in Nptn^-/- males support undisturbed hormonal regulation in the brain. However, Nptn^-/- males lack mounting behavior accompanied by low testosterone blood levels. Testosterone rise from juvenile to adult blood levels is absent in Nptn^-/- males. LH-receptor stimulation raising intracellular Ca²⁺ in Leydig cells triggers testosterone production. Reduced Plasma Membrane Ca²⁺ ATPase 1 (PMCA1) in Nptn^-/- Leydig cells suggests that Nptn^-/- Leydig cells produce sufficient testosterone for testis and sperm development, but a lack of PMCA-Np complexes prevents the increase from reaching adult blood levels. Behavioral immaturity with low testosterone blood levels underlies infertility of Nptn^-/- males, revealing that Np is essential for reproduction.