RESUMEN
Neurobeachin ( NBEA ) is a cytoplasmic protein that regulates receptor trafficking, neurotransmitter and hormone secretion, as well as synaptic connectivity. Recently, hippocampus-dependent contextual extinction, the gradual decrease of a conditioned fear response to a context, was suggested to be specifically impaired in male mice with Nbea deficiency ( Nbea+/- ). The current study examines the role of sex in this effect and whether Nbea also influences cued fear conditioning. We included both female and male mice and used a phased contextual and cued fear acquisition protocol that consists of different phases allowing us to assess fear acquisition, cued and contextual fear memory and within-phase extinction. Performance of Nbea+/- mice during assessment of both contextual and cued fear memory was significantly altered compared to controls, independent of sex. Follow-up analyses revealed that this altered performance could be indicative of impaired within-phase extinction. Altered within-phase extinction was not exclusively attributable to hippocampus, and independent of sex. Our results rather suggest that Nbea influences complex learning more broadly across different brain structures.
Asunto(s)
Condicionamiento Clásico , Extinción Psicológica , Miedo , Haploinsuficiencia , Proteínas de la Membrana , Proteínas del Tejido Nervioso , Animales , Femenino , Masculino , Ratones , Encéfalo/fisiología , Señales (Psicología) , Proteínas de la Membrana/genética , Memoria , Proteínas del Tejido Nervioso/genética , Factores Sexuales , Ratones Endogámicos C57BLRESUMEN
Autism spectrum disorder (ASD) is a common and pervasive neurodevelopmental disorder, characterized by sexually divergent social deficits. Its etiology is multifactorial with an important contribution of genetic factors. Neurobeachin (Nbea), a brain-enriched multidomain scaffolding protein, is an ASD candidate gene that was found to be translocated or deleted in ASD patients. Nbea haploinsufficient (+/-) mice have been proposed as an ASD mouse model, but its broad-spectrum social phenotype, sexual divergence and age-related robustness remain unstudied. This study compared one-year-old male and female Nbea+/- mice and their control littermates in an extensive behavioral battery that focused on social behaviors and communication. Nbea haploinsufficiency was associated with selective, sex-dependent, quantitative and qualitative changes, including alterations in social interest and approach, ultrasonic vocalization (USV) between same-sex adult conspecifics, and preferred types of social interaction. Notably, Nbea+/- females (but not males) displayed a significantly higher number of calls, and the mean principal frequency of their calls was higher than those of normal female littermates. Our results demonstrate that Nbea haploinsufficiency alters various aspects of social performance that are also altered in clinical ASD. The phenotype was often different between male and female mice, even though this sexual divergence was sometimes counterintuitive to observations in people with ASD, and probably influenced by differences in social interaction between male and female mice. By and large, however, this study demonstrates the clinical validity and robustness of the ASD-like phenotype of Nbea+/- mice.