Targeting VGLUT Machinery: Implications on mGluR5 Signaling and Behavior

Cross talk between both pre- and postsynaptic components of glutamatergic neurotransmission plays a crucial role in orchestrating a multitude of brain functions, including synaptic plasticity and motor planning. Metabotropic glutamate receptor (mGluR) 5 exhibits promising therapeutic potential for many neurodevelopmental and neurodegenerative disorders as a consequence of its modulatory control over diverse neuronal networks required for memory, motor coordination, neuronal survival, and differentiation. Given these crucial roles, mGluR5 signaling is under the tight control of glutamate release machinery mediated through vesicular glutamate transporters (VGLUTs) that ultimately dictate glutamatergic output. A particular VGLUT isoform, VGLUT3, exhibits an overlapping, but unique, distribution with mGluR5, and the dynamic cross talk between mGluR5 and VGLUT3 is key for the function of specific neuronal networks involved in motor coordination, emotions, and cognition. Thus, aberrant signaling of the VGLUT3-mGluR5 axis is linked to various pathologies including, but not limited to, Parkinson disease, anxiety disorders, and drug addiction. We argue that a comprehensive profiling of how coordinated VGLUT3-mGluR5 signaling influences overall glutamatergic neurotransmission is warranted. SIGNIFICANCE STATEMENT: Vesicular glutamate receptor (VGLUT) 3 machinery orchestrates glutamate release, and its distribution overlaps with metabotropic glutamate receptor (mGluR) 5 in regional brain circuitries, including striatum, hippocampus, and raphe nucleus. Therefore, VGLUT3-mGluR5 cross talk can significantly influence both physiologic and pathophysiologic glutamatergic neurotransmission. Pathological signaling of the VGLUT3-mGluR5 axis is linked to Parkinson disease, anxiety disorders, and drug addiction. However, it is also predicted to contribute to other motor and cognitive disorders.