Psychedelic neuroplastogen rescue of cognitive flexibily in autism spectrum disorder

About This Grant

PROJECT SUMMARY / ABSTRACT Increasing numbers of people, including adults, have been diagnosed with autism spectrum disorder (ASD). For people utilizing medications for ASD, results are often unsatisfactory and involve off-target effects, necessitating the identification of better treatments. This project will help address this significant gap in knowledge by investigating the ability of psychedelic drugs to normalize cognitive flexibility deficits and changes to prefrontal cortex circuits caused by Cntnap2 knockout (KO), a mouse model that captures some of the behavioral abnormalities associated with ASD, including cognitive rigidity. Cognitive flexibility, a fundamental process that is required for adaptive behavior, is compromised in many people with ASD. As the PFC is important for cognitive flexibility and control of behavior, ASD-related cognitive inflexibility may be correlated with the known alterations to density of dendritic spines, a proxy for synaptic connectivity, in prefrontal cortex pyramidal neurons. Similarly, decreases in cognitive flexibility, reductions in dendritic spine density, and attenuations in excitatory synaptic input to PFC pyramidal neurons have been reported in mouse models that capture ASD-associated behavioral phenotypes. In contrast, psychedelic treatment has been shown to improve cognitive flexibility, elevate dendritic spine density, and boost excitatory synaptic input to PFC pyramidal cells. Therefore, psychedelic-mediated repair of PFC circuits and associated flexible behaviors may represent a novel ASD treatment paradigm. Although psychedelic treatment is a promising target for both increasing reversal learning ability and enhancing PFC synaptic connectivity in people with major depression, it is unknown if psychedelic treatment is able to normalize cognitive flexibility alterations and repair neural circuits disrupted in ASD, leaving a critical unaddressed question. Here, using long-time scale behavioral measures of flexibility and synaptic morphophysiological analyses, we will test the central hypothesis that psychedelic treatment will improve reversal learning ability (Aim 1) and repair PFC circuit structure and function (Aim 2) that is compromised in the Cntnap2 KO mice. Successful completion of these aims has the potential to significantly improve our understanding of the utility of psychedelic medicine for the treatment of ASD, as this treatment paradigm holds the promise of improving flexible learning by fundamentally changing the underlying synaptic landscape in PFC.