Juvenile manifestation of ultrasound communication deficits in the neuroligin-4 null mutant mouse model of autism

Abstract

Neuroligin-4 (Nlgn4) is a member of the neuroligin family of postsynaptic cell adhesion molecules. Lossof-function mutations of NLGN4 are among the most frequent, known genetic causes of heritable autism.Adult Nlgn4 null mutant (Nlgn4−/−) mice are a construct valid model of human autism, with both gendersdisplaying a remarkable autistic phenotype, including deficits in social interaction and communication aswell as restricted and repetitive behaviors. In contrast to adults, autism-related abnormalities in neonataland juvenile Nlgn4−/− mice have not been reported yet. The present study has been designed tosystematically investigate in male and female Nlgn4−/− pups versus wildtype littermates (WT, Nlgn4+/+)developmental milestones and stimulus-induced ultrasound vocalization (USV). Neonatal development,followed daily from postnatal days (PND) 4 to 21, including physical development, neurological reflexesand neuromotor coordination, did not yield any differences between Nlgn4−/− and their WT littermates.USV in pups (PND8–9) in response to brief separation from their mothers revealed remarkable gendereffects, and a genotype influence in females regarding latency to first call. In juveniles (PND22–23),USV monitoring upon exposure to an anesthetized female intruder mouse uncovered a clear genotypeeffect with reduced USV in Nlgn4−/− mice, and again a more prominent phenotype in females. Together,these data support an early manifestation of communication deficits in Nlgn4−/− mice that appear morepronounced in immature females with their overall stronger USV as compared to males.