Syn3 Gene Knockout Negatively Impacts Aspects of Reversal Learning Performance

Behavioral flexibility enables the ability to adaptively respond to changes in contingency requirements to maintain access to desired outcomes, and deficits in behavioral flexibility have been documented in many psychiatric disorders. Previous research has shown a correlation between behavioral flexibility measured in a reversal learning test and Syn3, the gene encoding synapsin III, which negatively regulates phasic dopamine release. Syn3 expression in the hippocampus, striatum, and neocortex is reported to be negatively correlated with reversal learning performance, so here, we used a global knock-out line to investigate reversal learning in mice homozygous wild type, heterozygous null, and homozygous null for the Syn3 gene. Compared with wild-type animals, we found a reversal-specific effect of genetic Syn3 deficiency that resulted in a greater proportional increase in trials required to reach a preset performance criterion during contingency reversal, despite no observed genotype effects on the ability to acquire the initial discrimination. Behavioral flexibility scores, which quantified the likelihood of switching subsequent choice behavior following positive or negative feedback, became significantly more negative in reversal only for Syn3 homozygous-null mice, suggesting a substantial increase in perseverative behavior in the reversal phase. Syn3 ablation reduced the number of anticipatory responses made per trial, often interpreted as a measure of waiting impulsivity. Overall, Syn3 expression negatively affected behavioral flexibility in a reversal-specific manner but may have reduced waiting impulsivity.