New regime of presynaptic release regulation

Information processing in the brain is mediated by communication between excitable cells, called neurons, which form physical contacts termed synapses. In a synapse, the transmission of electrical signals from one neuron to the other occurs via the release of chemicals, called neurotransmitters. The neurotransmitters are packed in tiny synaptic vesicles in the presynaptic axon terminals, and these vesicles fuse to the terminal membrane when the presynaptic terminals are electrically activated. The released transmitters bind to their ionotropic receptors on the postsynaptic neurons, which convert the chemical signals back to electrical signals by opening ion pores within these receptors. The synaptic vesicle release can be regulated in various ways to control the strength and timing of the signal transmission through synapses. In classical views, a homogenous vesicle population was postulated whereby the fusion of these vesicles is triggered by the opening of voltage-gated calcium channels (VGCC) resulting in conformational changes in protein complexes called release machinery at the fusion sites. Depending on the frequency of the axon terminal activation and synapse types, the probability of vesicle release can be facilitated or depressed resulting in different modes of signal transmission. The number of release-ready vesicles and release probability can also be regulated by activating other types of receptors on the presynaptic membrane. In our previous studies, we discovered a peculiar regulatory mechanism of vesicle release in a specific neuronal pathway in the mouse brain, the medial habenula to interpeduncular nucleus pathway (MHb-IPN). In this pathway, facilitating and depressing modes of release can be switched by activating a specific type of receptor, the GABAB receptor, in the same terminal potentially involving two distinct vesicle populations associated with different molecules. The GABAB receptor normally inhibits the activation of VGCC and reduces the vesicle release probability in other synapses in the brain. Surprisingly, however, the same receptor activation in the MHb-IPN pathway drastically increased the vesicle release. These phenomena could only be observed in this pathway, indicating unprecedented mechanisms of vesicle release regulation in the MHb terminal. In the present project, we will identify the two types of synaptic vesicles with distinct molecular markers, differential dynamics of vesicle fusion and recycling, and signaling mechanisms downstream of GABAB receptor activation in this pathway. Our result will open a new regime of presynaptic regulation expanding our understanding of information processing in the brain.