RESUMEN
Somatosensory over-reactivity is common among patients with autism spectrum disorders (ASDs) and is hypothesized to contribute to core ASD behaviors. However, effective treatments for sensory over-reactivity and ASDs are lacking. We found distinct somatosensory neuron pathophysiological mechanisms underlie tactile abnormalities in different ASD mouse models and contribute to some ASD-related behaviors. Developmental loss of ASD-associated genes Shank3 or Mecp2 in peripheral mechanosensory neurons leads to region-specific brain abnormalities, revealing links between developmental somatosensory over-reactivity and the genesis of aberrant behaviors. Moreover, acute treatment with a peripherally restricted GABAA receptor agonist that acts directly on mechanosensory neurons reduced tactile over-reactivity in six distinct ASD models. Chronic treatment of Mecp2 and Shank3 mutant mice improved body condition, some brain abnormalities, anxiety-like behaviors, and some social impairments but not memory impairments, motor deficits, or overgrooming. Our findings reveal a potential therapeutic strategy targeting peripheral mechanosensory neurons to treat tactile over-reactivity and select ASD-related behaviors.
Asunto(s)
Trastorno del Espectro Autista/metabolismo , Agonistas del GABA/farmacología , Ácidos Isonicotínicos/farmacología , Fenotipo , Células Receptoras Sensoriales/efectos de los fármacos , Tacto/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Ansiedad/tratamiento farmacológico , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/genética , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Agonistas del GABA/uso terapéutico , Ácidos Isonicotínicos/uso terapéutico , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Proteína 2 de Unión a Metil-CpG/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Microfilamentos , Proteínas del Tejido Nervioso/genética , Inhibición Prepulso/efectos de los fármacos , Células Receptoras Sensoriales/metabolismoRESUMEN
The origin and fixation of evolutionarily young genes is a fundamental question in evolutionary biology. However, understanding the origins of newly evolved genes arising de novo from noncoding genomic sequences is challenging. This is partly due to the low likelihood that several neutral or nearly neutral mutations fix prior to the appearance of an important novel molecular function. This issue is particularly exacerbated in large effective population sizes where the effect of drift is small. To address this problem, we propose a regulation-focused, cultivator model for de novo gene evolution. This cultivator-focused model posits that each step in a novel variant's evolutionary trajectory is driven by well-defined, selectively advantageous functions for the cultivator genes, rather than solely by the de novo genes, emphasizing the critical role of genome organization in the evolution of new genes.