AMPAKINE enhancement of social interaction in the BTBR mouse model of autism

Abstract

Autism is a neurodevelopmental disorder in which the first diagnostic symptom is unusual reciprocal social interactions. Approximately half of the children diagnosed with an autism spectrum disorder also have intellectual impairments. General cognitive abilities may be fundamental to many aspects of social cognition. Cognitive enhancers could conceivably be of significant benefit to children and adults with autism. AMPAKINE compounds are a novel class of pharmacological agents that act as positive modulators of AMPA receptors to enhance excitatory glutamatergic neurotransmission. This class of compounds was reported to improve learning and memory in several rodent and non-human primate tasks, and to normalize respiratory abnormalities in a mouse model of Rett syndrome. Here we evaluate the actions of AMPA compounds in adult male and female BTBR mice, a well characterized mouse model of autism. Acute treatment with CX1837 and CX1739 reversed the deficit in sociability in BTBR mice on the most sensitive parameter, time spent sniffing a novel mouse as compared to time spent sniffing a novel object. The less sensitive parameter, time in the chamber containing the novel mouse versus time in the chamber containing the novel object, was not rescued by CX1837 or CX1739 treatment. Preliminary data with CX546, in which β-cyclodextrin was the vehicle, revealed behavioral effects of the acute intraperitoneal and oral administration of vehicle alone. To circumvent the artifacts introduced by the vehicle administration, we employed a novel treatment regimen using pellets of peanut butter for drug delivery. Absence of vehicle treatment effects when CX1837 and CX1739 were given in the peanut butter pellets, to multiple cohorts of BTBR and B6 control mice, confirmed that the pharmacologically-induced improvements in sociability in BTBR were not confounded by the administration procedures. The highest dose of CX1837 improved the cognitive deficit in novel object recognition in BTBR. No drug effects were detected on the high levels of repetitive self-grooming in BTBR. In open field tests, CX1837 and CX1739 did not induce hyperactivity or sedation in either strain. It is interesting to speculate that the ability of CX1837 and CX1739 to restore aspects of sociability in BTBR mice could utilize synaptic mechanisms regulating social cognition, suggesting a potential pharmacological target for interventions to treat symptoms of autism.

Long-Term Memory Deficits are Associated with Elevated Synaptic ERK1/2 Activation and Reversed by mGluR5 Antagonism in an Animal Model of Autism

“…B6 mice were chosen for comparison with BTBRs because they are extensively used in behavioral genetics, exhibit high levels of social approach (Bolivar et al, 2007;McFarlane et al, 2008;Yang et al, 2007), and have been used for comparison with BTBRs in previous work (Babineau et al, 2013;Silverman et al, 2013;Wohr et al, 2011;Yang et al, 2012). Mice were standard grouphoused with littermates in rooms maintained at 68 1C and 55% humidity, with 12 h on/12 h off light cycle, and food and water ad libitum.…”

“…There is now a large literature demonstrating disturbances in spine morphology and signaling cascades at excitatory synapses in animal models of cognitive disability (Belichenko et al, 2007;Kramar et al, 2012), including disorders on the autism spectrum (Chen et al, 2010;Hung et al, 2008;Seese et al, 2012;Tropea et al, 2009). Learning and executive functions are impaired in BTBR mice (Amodeo et al, 2012;Lipina and Roder, 2013;MacPherson et al, 2008;Ribeiro et al, 2013;Rutz and Rothblat, 2012;Silverman et al, 2013;Yang et al, 2012), but thorough analyses of associated synaptic abnormalities and evidence for pharmacological normalization of these measures are lacking.…”

Oral delivery of ivermectin using a fast dissolving oral film: Implications for repurposing ivermectin as a pharmacotherapy for alcohol use disorder

“…Current methods of oral delivery, including oral gavage (Brown, Dinger, & Levin, 2000; Germann & Ockert, 1994; Zhang, 2011), peanut butter mixture (Silverman, Oliver, Karras, Gastrell, & Crawley, 2013), gelatin molds (Froehlich, Hausauer, Federoff, Fischer, & Rasmussen, 2013), adding the drug to drinking water or a sucrose solution, and using pre-mixed drug-chocolate pellets (Zhang, 2011), all have significant limitations that can jeopardize the reliability of the data. Taken together, the disadvantages associated with the current methods of drug delivery have prompted interest in developing alternative methods to improve oral delivery in rodents, such as pre-coating the gavage needle with sucrose (Hoggatt et al, 2010).…”

Modeling psychiatric disorders for developing effective treatments

“…For instance, comparison of the inbred mouse strain BTBR T+tf/J with the inbred mouse strain C57/BL6 reveals that these mice show relatively less reciprocal social interaction, more grooming and different ultrasonic vocalizations 10 . Thus the BTBR mice have been proposed to be used as an autism model with high face validity and are used for ongoing preclinical drug testing 11,12 .…”