Characterization of early communicative behavior in mouse models of neurofibromatosis type 1

Abstract

Scientific Abstract 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 (Nf1GFAPCKO mice). We observed altered USV production in both models: Nf1+/− mice exhibited both increased USVs across development and alterations in aspects of pitch, while Nf1GFAPCKO 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.

NF1-cAMP signaling dissociates cell type–specific contributions of striatal medium spiny neurons to reward valuation and motor control

“…Along this line, several genetic models with mutations in the orthologs of the human NF1 gene have been created and shown to recapitulate many aspects of the disease, including tumor formation and cognitive and behavioral impairments [58,59]. For instance, Nf1 haploinsufficient ( Nf1 +/– ) mouse model has shown impaired spatial learning and memory in the Morris water maze and social recognition deficits [36,60], as well as impairments in early social communicative behaviors [61]. Interestingly, some of these behavioral deficits have been attributed to altered striatal dopamine levels [62].…”

Examining the Reversibility of Long-Term Behavioral Disruptions in Progeny of Maternal SSRI Exposure

“…Tissue from a toe was also collected at this time on P5 for genotyping. Frequency sonograms were prepared from recordings in MATLAB [frequency range = 25–120 kHz, FFT (Fast Fourier Transform) size = 512, overlap = 50%, time resolution = 1.024 ms, frequency resolution = 488.2 Hz], and individual syllables and other spectral features were identified and counted from the sonograms according to a previously published method ( Dougherty et al, 2013 ; Rieger and Dougherty, 2016 ; Maloney et al, 2018 ), adapted from validated procedures ( Holy and Guo, 2005 ).…”

Shared developmental gait disruptions across two mouse models of neurodevelopmental disorders

“…Crucially, the use of a patient-derived mutation in our Nf1 model represents an increasingly feasible precision medicine approach to disease modeling, setting an example for how mouse models can be used in future studies of NDD mechanisms and interventions. There are multiple other genetically-engineered mouse models of Nf1 mutations, both artificial (Brannan et al, 1994;Costa et al, 2002;Jacks et al, 1994;Maloney et al, 2018) and patient-derived mutations (Guo et al, 2019;Li et al, 2016;Toonen et al, 2016), which can be similarly assessed for gait function and compared to the present findings. Identification of the similarities and differences in gait phenotype across different Nf1 models will allow for better identification of and interventions for the various motor deficits seen in NF1 clinical populations.…”