The BTBR Mouse Model of Autism Spectrum Disorders Has Learning and Attentional Impairments and Alterations in Acetylcholine and Kynurenic Acid in Prefrontal Cortex

Abstract

Autism is a complex spectrum of disorders characterized by core behavioral deficits in social interaction, communication, repetitive stereotyped behaviors and restricted interests. Autism frequently presents with additional cognitive symptoms, including attentional deficits and intellectual disability. Preclinical models are important tools for studying the behavioral domains and biological underpinnings of autism, and potential treatment targets. The inbred BTBR T+tf/J (BTBR) mouse strain has been used as an animal model of core behavioral deficits in autism. BTBR mice exhibit repetitive behaviors and deficits in sociability and communication, but other aspects of their cognitive phenotype, including attentional performance, are not well characterized. We examined the attentional abilities of BTBR mice in the 5-choice serial reaction time task (5-CSRTT) using an automated touchscreen testing apparatus. The 5-CSRTT is an analogue of the human continuous performance task of attention, and so both the task and apparatus have translational relevance to human touchscreen cognitive testing. We also measured basal extracellular levels of a panel of neurotransmitters within the medial prefrontal cortex, a brain region critically important for performing the 5-CSRTT. We found that BTBR mice have increased impulsivity, defined as an inability to withhold responding, and decreased motivation, as compared to C57Bl/6J mice. Both of these features characterize attentional deficit disorders in humans. BTBR mice also display decreased accuracy in detecting short stimuli, lower basal levels of extracellular acetylcholine and higher levels of kynurenic acid within the prefrontal cortex. Intact cholinergic transmission in prefrontal cortex is required for accurate performance of the 5-CSRTT, consequently this cholinergic deficit may underlie less accurate performance in BTBR mice. Based on our findings that BTBR mice have attentional impairments and alterations in a key neural substrate of attention, we propose that they may be valuable for studying mechanisms for treatment of cognitive dysfunction in individuals with attention deficits and autism.

Acetylcholine Elevation Relieves Cognitive Rigidity and Social Deficiency in a Mouse Model of Autism

“…Recent studies demonstrated that low levels of ACh (McTighe et al, 2013) and reduction in striatal size (Ellegood et al, 2013b) accompany the aberrant behavior of this strain. Additionally, recent indirect evidence suggests E/I imbalance involvement in BTBR symptomology, as pharmacological modulation of glutamatergic synapses rescues these behaviors (Silverman et al, 2012).…”

“…As an animal model, we used the BTBR T þ tf/J mouse strain, which is considered a reliable preclinical model for autism due to its distinct behavioral abnormalities resembling ASD symptoms including impaired social behavior, aberrant communication, increased repetitive behavior, and increased cognitive rigidity (reviewed in (Chadman and Guariglia, 2012)). Importantly, recent studies identified abnormally lower basal levels of brain ACh in BTBR mice compared with C57BL/6 mice (McTighe et al, 2013). …”

Dissociable Deficits of Executive Function Caused by Gestational Adversity are Linked to Specific Transcriptional Changes in the Prefrontal Cortex

“…Only a response at the correct hole during the stimulus or limited hold was reinforced. Performance measures (correct, premature, and incorrect responses, and omissions) were reported as a percentage of the total number of trials (the sum of correct, premature, incorrect, and omitted trials) (McTighe et al, 2013;Scott and Taylor, 2014).…”

The NEWMEDS rodent touchscreen test battery for cognition relevant to schizophrenia

“…When VAChT was overexpressed, mice displayed a profile of both impaired attention and impulsivity at shorter stimulus durations, with reduced accuracy and increased premature responding, respectively (Kolisnyk et al 2013a, b). The task has also been used to assess a model of autism, the inbred BTBR T+tf/J mouse, which also showed reduced levels of prefrontal acetylcholine (McTighe et al 2013). As in Kolisnyk et al (2013b), these mice showed impaired acquisition.…”