Identification of the presynaptic function of the serine/threonine kinase, LKB1

Chemical synapses represent the close apposition between the presynaptic terminal of an axon and the dendrite of another neuron and is essential for proper neurotransmission i.e. for brain function. Despite decades of research, the molecular mechanisms underlying presynaptic differentiation of growing axons are still poorly understood especially in mammalian neurons. Synapse formation is the ultimate expression of neuronal polarization during which axons and dendrites acquire a set of distinct molecular and functional specialization. On the presynaptic side, axons accumulate through directed trafficking the specialized neurotransmitter-filled vesicles and the proteins required for fast presynaptic release. What are the signaling mechanisms regulating this last step of axonal development? We hypothesized that the kinase LKB1 which is critical for the establishment of an axon during neuronal polarization [1,2] as well as axon growth and terminal branching (Courchet and Polleux, in preparation) might also be involved in presynaptic differentiation. We have accumulated preliminary results showing that genetic deletion of LKB1 in cortical neurons after axon formation critically impairs presynaptic vesicle trafficking and results in severe behavioral locomotor deficits. We therefore propose to test (1) the exact molecular mechanisms underlying the function of LKB1 in presynaptic differentiation, (2) the upstream and downstream mechanisms regulating LKB1 function during presynaptic development and (3) the electrophysiological and behavioral evaluation of the consequences of inhibiting LKB1 on presynaptic function.