Subventions et des contributions :

Subvention ou bourse octroyée s'appliquant à plus d'un exercice financier. (2017-2018 à 2022-2023)

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.
We recently observed that VAChT or VGLUT3 are sorted to different populations of SVs in TANS. The objective of our proposal is to better understand molecular mechanisms underlying the vesicular sorting of VAChT or VGLUT3 in TANS. This will help to identify original molecular targets involved in the regulation of striatal networks. In particular, different types of calcium channels (L, N, P, and Q channels) critically regulate neurotransmitter release. These calcium channels have different kinetics properties and are often coupled to either single spike or bursting activity of neurons. In addition, nothing is known on how VGLUT3 and VAChT influence each other vesicular sorting.
In this context, we propose 2 major tasks: i) to identify which synaptic proteins such as synaptotagmins or calcium channels associated with VAChT- or VGLUT3-positive SVs and ii) to clarify how VAChT or VGLUT3 impact on each other synaptic targeting.
The major outcome of this research will be a better understanding of TANS, a pivotal neuronal population with unique properties. This knowledge will fuel research on striatal functions such as locomotor activity, habits- or reward-guided behaviors. Therefore pathologies as diverse as Parkinson’s disease, obsessive-compulsive disorders or addiction could benefits from basic knowledge that will emerge from our investigations.