Genetic influences of autism candidate genes on circuit wiring and olfactory decoding

Abstract

Olfaction supports a multitude of behaviors vital for social communication and interactions between conspecifics. Intact sensory processing is contingent upon proper circuit wiring. Disturbances in genetic factors controlling circuit assembly and synaptic wiring can lead to neurodevelopmental disorders, such as autism spectrum disorder (ASD), where impaired social interactions and communication are core symptoms. The variability in behavioral phenotype expression is also contingent upon the role environmental factors play in defining genetic expression. Considering the prevailing clinical diagnosis of ASD, research on therapeutic targets for autism is essential. Behavioral impairments may be identified along a range of increasingly complex social tasks. Hence, the assessment of social behavior and communication is progressing towards more ethologically relevant tasks. Garnering a more accurate understanding of social processing deficits in the sensory domain may greatly contribute to the development of therapeutic targets. With that framework, studies have found a viable link between social behaviors, circuit wiring, and altered neuronal coding related to the processing of salient social stimuli. Here, the relationship between social odor processing in rodents and humans is examined in the context of health and ASD, with special consideration for how genetic expression and neuronal connectivity may regulate behavioral phenotypes.

Keywords: Behavior; Mice; Olfaction; Shank2; Social; Synaptic wiring.

Fig. 1

Social behavior assessment in murine models. Social interactions can be studied using behavioral assays, where the behaviors observed in different settings help inform the role of social cues. Such assays aid in isolating specific sensory components from an interaction experience. Social behaviors include interactions with a offspring, facilitating maternal behavior (top), such as pup retrieval, and from conspecifics which can elicit aggressive behaviors (bottom). The b food preference test and c sociability (left) and social novelty preference (right) tests can also be implemented in a d 3-chamber testing arena where social cues can be positioned at each end of a linearly oriented row of chambers, consisting for instance, of a neutral middle zone where test animals make a decision where to spend most time exerting exploratory behavior. e A housing environment where odor and water ports have been integrated to run conditioning paradigms and examine group behavior (e.g., social hierarchies). Figure utilized BioRender for standard graphical illustrations

Fig. 2

Primary circuit wiring for olfaction and oxytocin. The primary olfactory processing circuitry is depicted alongside oxytocin projection sites. Incoming stimuli (e.g., social odorants) are first processed by the MOB before relay to the AON, PCx, and the Amy. Recurrent projections between bottom-up and top-down processing streams are illustrated by the double-sided arrows. The central hub for oxytocin production, the PVN, is shown projecting to downstream effector targets that can have a direct or indirect effect on olfactory processing. Abbreviations: AMY amygdala; AON anterior olfactory nucleus; dHipp and vHipp the dorsal and ventral hippocampus, respectively; MOB: main olfactory bulb; PCx piriform cortex; PVN paraventricular nucleus of the hypothalamus