Neurofibromatosis type 1 (NF1) is a monogenic neurodevelopmental disease caused by germline loss-of-function mutations in the NF1 tumor suppressor gene. Cognitive impairments are observed in approximately 80% of children with this disease, with 45–60% exhibiting autism spectrum disorder (ASD) symptomatology. In light of the high comorbidity rate between ASD and NF1, we assessed early communicative behavior by maternal-separation induced pup ultrasonic vocalizations (USV) and developmental milestones in two distinct Nf1 genetically engineered models, one modeling clinical germline heterozygous loss of Nf1 function (Nf1 +/– mice), and a second with somatic biallelic Nf1 inactivation in neuroglial progenitor cells (Nf1 GFAP CKO mice). We observed altered USV production in both models: Nf1 +/– mice exhibited both increased USVs across development and alterations in aspects of pitch, while Nf1 GFAP CKO mice demonstrated a decrease in USVs. Developmental milestones, such as weight, pinnae detachment, and eye opening, were not disrupted in either model, indicating the USV deficits were not due to gross developmental delay, and likely reflected more specific alterations in USV circuitry. In this respect, increased whole-brain serotonin was observed in Nf1 +/– mice, but whole-brain levels of dopamine and its metabolites were unchanged at the age of peak USV disruption, and USV alterations did not correlate with overall level of neurofibromin loss. The early communicative phenotypes reported herein should motivate further studies into the risks mediated by haploinsufficiency and biallelic deletion of Nf1 across a full battery of ASD-relevant behavioral phenotypes, and a targeted analysis of underlying circuitry disruptions. Autism Res 2018, 11: 44–58.
- neurofibromatosis type 1
- ultrasonic vocalization