Protein O-GlcNAcylation is a
post-translational modification that links environmental stimuli with changes in intracellular
signal pathways, and its disturbance has been found in
neurodegenerative diseases and metabolic disorders. However, its
role in the mesolimbic
dopamine (DA) system, especially in the
ventral tegmental area (VTA),
needs to be elucidated. Here, we found that
injection of Thiamet G, an O-GlcNAcase (OGA) inhibitor, in the VTA and
nucleus accumbens (NAc) of
mice, facilitated neuronal O-GlcNAcylation and decreased the operant response to
sucrose as well as the latency to fall in
rotarod test.
Mice with DAergic
neuron-specific knockout of O-GlcNAc
transferase (OGT) displayed severe metabolic
abnormalities and died within 4-8 weeks after
birth. Furthermore,
mice specifically overexpressing OGT in DAergic
neurons in the VTA had
learning defects in the operant response to
sucrose, and impaired motor
learning in the
rotarod test. Instead, overexpression of OGT in
GABAergic neurons in the VTA had no effect on these
behaviors. These results suggest that
protein O-GlcNAcylation of DAergic
neurons in the VTA
plays an important
role in regulating the response to natural
reward and motor
learning in
mice.