Abstract
Stereotypic and/or repetitive behavior is one of the major symptoms of autism spectrum disorder (ASD). Increase of self-grooming behavior is a behavioral phenotype commonly observed in the mouse models for ASD. Previously, we have shown that knockout of acid-sensing ion channel 3 (ASIC3) led to the increased self-grooming behavior in resident-intruder test. Given the facts that ASIC3 is mainly expressed in the peripheral dorsal root ganglion (DRG) and conditional knockout of ASIC3 in the proprioceptors induced proprioception deficits. We speculate a hypothesis that stereotypic phenotype related to ASD, pararalled with striatal dysfunction, might be caused by proprioception defect in the peripheral sensory neuron origin. Herein, we investigate in depth whether and how ASIC3 is involved in the regulation of self-grooming behavior. First, we observed that Asic3 null mutant mice exhibited increased self-grooming in social interaction during juvenile stage. Similarly, they displayed increased self-grooming behavior in a novel cage in the absence of cagemate. To further understand the mechanism by which ASIC3 affects grooming behavior, we analyzed neurochemical, neuropathological and electrophysiological features in the dorsal striatum of Asic3 null mutant mice. Knockout of Asic3 increased dopamine (DA) activity and phospho-ERK immunoreactivities in the dorsal striatum. Furthermore, we detected a lower paired-pulse ratio (PPR) and impaired long-term potentiation (LTP) in corticostriatal circuits in Asic3 null mutant mice as compared with wild-type (WT) littermates. Moreover, knockout of Asic3 altered the medial spiny neurons in the striatum with defects in presynaptic function and decrease of dendritic spines. Lastly, genetic ablation of Asic3 specifically in parvalbumin-positive (PV+) cells resulted in the increase of self-grooming behavior in mice. These findings suggest knockout of Asic3 in the PV+ neurons alters grooming behavior by co-opting corticostriatal circuits.
Highlights
Self-grooming is an innate behavior that can be observed across multiple species (Kalueff et al, 2016)
Behavior analysis, neuropathology, neurochemistry, and electrophysiology, we demonstrated that mutation of proprioceptive acid-sensing ion channel 3 (ASIC3) may result in increased grooming behavior in mice with dysregulation of the corticostriatal circuit
To understand whether the increase of stereotypic behavior is a general phenotype for Asic3−/− mice or a phenotype induced by social stress, we examined the stereotypic behavior during reciprocal social interaction in juvenile Asic3−/− mice with a same sex, strain, and similar age stranger mouse which is less stressful to the subject
Summary
Self-grooming is an innate behavior that can be observed across multiple species (Kalueff et al, 2016). Excessive self-grooming behavior in rodents is a significant stereotypic and/or repetitive behavior that could be directly linked to psychiatric disorders such as autism spectrum disorder (ASD) and obsessivecompulsive disorder (OCD; Silverman et al, 2010; Langen et al, 2011; Ting and Feng, 2011; Shepherd, 2013). Grooming behavior in rodents directly involves the animal’s own face, whiskers, and body. The neural circuits underlying self-grooming behavior had been extensively investigated. Most of the evidence indicate that corticostriatal circuits is involved in the control of self-grooming behavior (Burguière et al, 2013; Kalueff et al, 2016)
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