Phenotypic Behavioural Effects of Genetic Deletion of the Vesicular Glutamate Transporter 3 in 5‐Hydroxytryptamine Neurons

A major subpopulation of 5‐hydroxytryptamine (5‐HT) neurons expresses the vesicular glutamate transporter 3 (VGLUT3) allowing the co‐release of glutamate. Previous evidence has implicated VGLUT3 in 5‐HT neurons in mechanisms of anxiety and reward. Here we examined mice with a genetic loss of VGLUT3 targeted to 5‐HT neurons (VGLUT3 cKO 5‐HT ) and littermate controls in a battery of behavioural tests, including paradigms assessing levels of anxiety and learning with appetitive rewards. Compared to littermate controls, VGLUT3 cKO 5‐HT mice displayed no evidence of altered anxiety‐like behaviour in the elevated plus maze, light/dark box, marble burying and social interaction tests. However, VGLUT3 cKO 5‐HT mice showed reduced preference for low (but not high) sucrose‐containing solution and reduced correct responses in an appetitively motivated spatial reference memory task. Similarly, in an appetitively motivated operant task, VGLUT3 cKO 5‐HT mice displayed evidence of reduced responding to cues associated with reward. These effects appeared specific in that VGLUT3 cKO 5‐HT mice did not differ from controls in terms of home cage food consumption, performance in a spatial novelty preference test, as well as contextual and cued fear memory tests. These findings support a role for VGLUT3 in 5‐HT neurons in some aspects of learning, here in association with learning for reward, although not anxiety‐like behaviour.