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

Serotonergic dysregulation is implicated in numerous psychiatric disorders. Serotonin plays widespread trophic roles during neurodevelopment; thus perturbations to this system during development may increase risk for neurodevelopmental disorders. Epidemiological studies have examined association between selective serotonin reuptake inhibitor (SSRI) treatment during pregnancy and increased autism spectrum disorder (ASD) risk in offspring. It is unclear from these studies whether ASD susceptibility is purely related to maternal psychiatric diagnosis, or if treatment poses additional risk. We sought to determine whether maternal SSRI treatment alone or in combination with genetically vulnerable background was sufficient to induce offspring behavior disruptions relevant to ASD. We exposed C57BL/6J or Celf6+/- mouse dams to fluoxetine (FLX) during different periods of gestation and lactation and characterized offspring on tasks assessing social communicative interaction and repetitive behavior patterns including sensory sensitivities. We demonstrate robust reductions in pup ultrasonic vocalizations (USVs) and alterations in social hierarchy behaviors, as well as perseverative behaviors and tactile hypersensitivity. Celf6 mutant mice demonstrate social communicative deficits and perseverative behaviors, without further interaction with FLX. FLX re-exposure in adulthood ameliorates the tactile hypersensitivity yet exacerbates the dominance phenotype. This suggests acute deficiencies in serotonin levels likely underlie the abnormal responses to sensory stimuli, while the social alterations are instead due to altered development of social circuits. These findings indicate maternal FLX treatment, independent of maternal stress, can induce behavioral disruptions in mammalian offspring, thus contributing to our understanding of the developmental role of the serotonin system and the possible risks to offspring of SSRI treatment during pregnancy.

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

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 (Nf1GFAP 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 Nf1GFAP 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. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Neurofibromatosis type 1 (NF1) is a common neurogenetic disorder caused by mutation of the NF1 gene, in which 80% of affected children exhibit cognitive and behavioral issues. Based on emerging evidence that NF1 may be an autism predisposition gene, we examined autism spectrum disorder (ASD)-relevant early communicative behavior in Nf1 mouse models and observed alterations in both models. The changes in early communicative behavior in Nf1 mutant mice should motivate further studies into the causative factors and potential treatments for ASD arising in the context of NF1.