Social behavioral deficits in NF1 emerge from peripheral chemosensory neuron dysfunction

Abstract

Neurofibromatosis type 1 (NF1) is a neurodevelopmental disorder commonly associated with social and communicative disabilities. The cellular and circuit mechanisms by which loss of neurofibromin 1 (Nf1) function results in social deficits are unknown. Here, we identify social behavioral dysregulation with loss of Nf1 in Drosophila. These deficits map to primary dysfunction of a small group of peripheral sensory neurons, rather than central brain circuits.Specifically, Nf1 regulation of Ras signaling in adult, Ppk23+ chemosensory cells is required for normal social behaviors in flies. Loss of Nf1 results in attenuated ppk23+ neuronal activity in response to pheromonal cues, and circuit-specific manipulation of Nf1 expression or neuronal activity in ppk23+ neurons rescues social deficits. Unexpectedly, this disrupted sensory processing gives rise to persistent changes in behavior lasting beyond the social interaction, indicating a sustained effect of an acute sensory misperception. Together our data identify a specific circuit mechanism through which Nf1 acts to regulate social behaviors, and suggest social deficits in NF1 arise from propagation of sensory misinformation. and sleep abnormalities, learning and memory deficits, hyperactivity, and repetitive grooming behavior (The et al. van der Voet et al., 2016;Bai et al., 2018). Disruption of the conserved signaling pathways downstream of Nf1, Ras-MAPK and/or cAMP-PKA, has been implicated in these phenotypes. The genetic tractability of Drosophila also provides unique opportunities to study how social behaviors are affected by the function of genes, such as Nf1, that are associated with neurodevelopmental disorders (NDDs) and ASDs. Previous work has described social deficits with mutation of fly homologs of the Fragile X Mental Retardation gene (dFMR1) and ASD-candidate genes such as neurobeachin (rugose) and Neuroligin (Dnlg-2 and Dnlg-4) (Bolduc et al., 2010;Hahn et al., 2013;Wise et al., 2015;Corthals et al., 2017). The underlying neuronal circuitry that governs social interactions in flies is precisely mapped (Clowney et al., 2015;Kallman, Kim and Scott, 2015), facilitating the examination of how Nf1 modulates such behaviors with circuit level resolution.Normally, a male fly responds to a female fly with courtship and to another male fly with rejection. Peripheral sensory neurons in antenna, legs, and mouth detect sex-specific cuticular hydrocarbons (CHCs) on the cuticle of other animals. This flow of sensory information modulates the activity of neurons in the brain to promote or suppress social interactions. In wild-type (WT) Drosophila melanogaster males, chemosensory detection of female-specific pheromones activates P1 'command' neurons to promote social interaction and courtship, while detection of male-derived pheromones suppresses P1 activity and inhibits courtship (Billeter et al., 2009;Clowney et al., 2015;Kallman, Kim and Scott, 2015). Disrupted function of specific groups of sensory neurons leads to aberrant social interactions between flies (Moon et...