NEGR1 Modulates Mouse Affective Discrimination by Regulating Adult Olfactory Neurogenesis.

ABSTRACT

Background: Affective recognition and sensory processing are impaired in people with autism. However, no mouse model of autism comanifesting these symptoms is available, thereby limiting the exploration of the relationship between affective recognition and sensory processing in autism and the molecular mechanisms involved. Methods: With Negr1 -/- mice, we conducted the affective state discrimination test and an odor habituation/dishabituation test. Data were analyzed using the k-means clustering method. We also employed a whole-cell patch clamp and bromodeoxyuridine incorporation assay to investigate underlying mechanisms. Results: When encountering mice exposed to restraint stress or chronic pain, wild-type mice discriminated between them by either approaching the stressed mouse or avoiding the painful mouse, whereas Negr1 -/- mice showed unbiased social interactions with them. Next, we demonstrated that both wild-type and Negr1 -/- mice used their olfaction for social interaction in the experimental context, but Negr1 -/- mice showed aberrant olfactory habituation and dishabituation against social odors. In electrophysiological studies, inhibitory inputs to the mitral cells in the olfactory bulb were increased in Negr1 -/- mice compared with wild-type mice, and subsequently their excitability was decreased. As a potential underlying mechanism, we found that adult neurogenesis in the subventricular zone was diminished in Negr1 -/- mice, which resulted in decreased integration of newly generated inhibitory neurons in the olfactory bulb. Conclusions: NEGR1 contributes to mouse affective recognition, possibly by regulating olfactory neurogenesis and subsequent olfactory sensory processing. We propose a novel neurobiological mechanism of autism-related behaviors based on disrupted adult olfactory neurogenesis.

A deficit in affective discrimination is one of the major symptoms of autism spectrum disorder, the molecular/cellular mechanisms of which have yet to be explored. Here, we demonstrated that Negr1-deficient autism-relevant mice did not show preferential social interaction with affectively provoked mice (i.e., stress and pain) and showed its association with aberrant olfactory processing for other mice. As a potential underlying cellular mechanism, we found a decrease in adult-born neurons and excitatory/inhibitory imbalance in the olfactory bulb region. These results suggest that further investigation into the role of Negr1 and olfactory processing could provide valuable insights into molecular and cellular mechanisms of autism.