Peer Review #2 of "Inducible nitric oxide synthase (NOS2) knockout mice as a model of trichotillomania (v0.1)"

Abstract

Background: trichotillomania (TTM) is an impulse control disorder characterized by repetitive hair pulling/trimming. Barbering behavior (BB) observed in laboratory animals is proposed as a model of TTM. The neurobiological basis of TTM is unclear, but involves striatal hyperactivity and hypoactivation of the prefrontal cortex. Methods: in this study, we evaluated the BB in knockout mice for the inducible isoform of nitric oxide synthase (NOS2KO) and the consequences of silencing this enzyme in PC12 cell differentiation. Results: NOS2KO exhibit exacerbated BB, starting 4 weeks of age, and increased repetitive movements compared to wild-type mice (WT). The expression of BB was attenuated by repeated treatment with clomipramine, a clinically approved drug to treat TTM in humans, or memantine, an antagonist of NMDA receptors, as well as partial rescue of NOS2 expression in haploinsufficient animals. The silencing of NOS2 expression reduced the MAP2 (microtubule-associated protein 2) levels in activity-induced differentiated PC12 cells. Discussion: our data led us to propose that NOS2 is putatively involved in the neuronal maturation of the inhibitory afferent pathways during neurodevelopment, and such inadequate inhibition of motor programs might be associated to the observed phenotype.