Regulation of the striatal network by glutamate and acetylcholine co-transmission.

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Neurons communicate with electrochemical signals. Chemical messengers, or neurotransmitters, are accumulated inside synaptic vesicles (SV) before their calcium-dependent release. Glutamate (glut) the major excitatory transmitter in the brain is concentrated inside SV by vesicular transporter named VGLUT1-3. Our team made the surprising discovery that VGLUT3 is expressed by neurons using other neurotransmitters than glutamate. VGLUT3 is present used by all striatal cholinergic interneurons (also named Tonically Active Neurons or TANS). Therefore, TANS signal with both acetylcholine (ACh) and glut. The consequences of ACh/glut cotransmission recently started to be investigated. For example, we established that VGLUT3 null mice are hyperactive and more sensitive to cocaine. This is essentially due to an increased dopamine signaling in the nucleus accumbens in the absence of VGLUT3. Interestingly, silencing ACh signaling in TANS by specific ablation of the vesicular ACh transporter (VAChT) has opposite effects. Therefore, the dual ACh/glut transmission provides TANS with complex regulatory properties of striatal networks.