Allosteric modulation of nicotinic and GABA(A) receptor subtypes differentially modify autism-like behaviors in the BTBR mouse model

作者：Yoshimura Ryan F; Tran Minhtam B; Hogenkamp Derk J; Ayala Narielle L; Johnstone Timothy; Dunnigan Andrew J; Gee Timothy K; Gee Kelvin W

来源：Neuropharmacology, 2017, 126: 38-47.

DOI：10.1016/j.neuropharm.2017.08.029

• Autism
• BTBR
• GABA
• Nicotinic
• Allosteric modulator

Autism spectrum disorder (ASD) is associated with two core symptoms (social communication deficits and stereotyped repetitive behaviors) in addition to a number of comorbidities. There are no FDA-approved drugs for the core symptoms and the changes that underlie these behaviors are not fully understood. One hypothesis is an imbalance of the excitation (E)/inhibition (I) ratio with excessive E and diminished I occurring in specific neuronal circuits. Data suggests that both gamma-aminobutyric acid(A) (GABA(A)) and alpha 7 nicotinic acetylcholine receptors (nAChRs) significantly impact E/I. BTBR T+ tf/J (BTBR) mice are a model that display an autism-like phenotype with impaired social interaction and stereotyped behavior. A beta 2/3-subunit containing GABA(A) receptor (GABA(A)R) subtype selective positive allosteric modulator (PAM), 2-261, and an alpha 7 nAChR subtype selective PAM, AVL-3288, were tested in social approach and repetitive self-grooming paradigms. 2-261 was active in the social approach but not the self-grooming paradigm, whereas AVL-3288 was active in both. Neither compound impaired locomotor activity. Modulating a7 nAChRs alone may be sufficient to correct these behavioral and cognitive deficits. GABAergic and nicotinic compounds are already in various stages of clinical testing for treatment of the core symptoms and comorbidities associated with ASD. Our findings and those of others suggest that compounds that have selective activities at GABA(A)R subtypes and the alpha 7 nAChR may address not only the core symptoms, but many of the associated comorbidities as well and warrant further investigation in other models of ASD.

• 出版日期2017-11