Control of long-term synaptic plasticity by transsynaptic cell adhesion molecules

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Long-term potentiation (LTP) is a phenomenon of synapse strengthening caused by recent neuronal activity patterns, which results in an increase of transmission between two neurons. It is accepted as one of the key processes underlying synaptic plasticity that is crucial for learning and memory. Despite the many studies on long-term synaptic plasticity during the past half century, the fundamental mechanisms that mediate LTP remain largely unknown, and the biological significance of LTP is incompletely understood. Recent advances in the field have uncovered an unexpected role of synaptic cell adhesion molecules in LTP. While their very name primarily evokes a mechanical function, synaptic cell adhesion molecules were discovered to mediate bidirectional signalling and contribute to the specification of pre- and postsynaptic properties. Therefore the present project is guided by the hypothesis that these neuronal cell adhesion molecules may mediate trans-synaptic signalling, which may explain and uncover some of the unknown molecular mechanisms in LTP. The project will focus on Leucine-rich repeat transmembrane proteins (LRRTMs), postsynaptic cell-adhesion ligands, which role in the synapses has just begun to be explored. I will address four main points to elucidate the role of LRRTMs in LTP. First, I will describe the fundamental role of LRRTMs in LTP in conditional knock-out mice. Second, I will search for molecular interactions of LRRTMs with effector proteins to identify potential LTP-relevant signalling pathways. Third, I will test the significance of these signalling pathways in vivo. Finally, I will examine the effect of hippocampal LRRTM manipulations on spatial learning to determine more specifically the role of LTP in memory. This project will pursue hypotheses that are novel, and if proven correct, will stimulate work in an entirely new area of neuronal cell biology. The notion that postsynaptic LTP requires enabling by trans-synaptic cell-adhesion molecules represents a fundamental conceptual innovation in the LTP field in which a potential presynaptic contribution to LTP traditionally is ruled out and therefore has broad implications for work in many areas of molecular, cellular, and behavioural neuroscience. This topic also has great potential for advancing understanding of the pathophysiology of mental illnesses given the genetic association between LRRTMs and disorders such as schizophrenia, and autism-associated disorders.