Control of long-term synaptic plasticity by transsynaptic cell adhesion molecules
Final Report Abstract
Long-term potentiation (LTP) provides a compelling cellular model for learning and memory. It is a phenomenon of synapse strengthening caused by recent neuronal activity between two neurons. Although LTP has been extensively studied, the molecular mechanism of AMPAR insertion during LTP is still incompletely understood. Recent findings indicate that the role of certain cell-adhesion molecules might pave the way to elucidate functional and structural mechanisms of LTP. Neuroligin (Nlgn) is a postsynaptic cell-adhesion molecule, which heterophilically binds to presynaptic Neurexins (Nrxns) and thereby stabilizes and specifies synapses. The intracellular domain of Nlgn is shown to bind PSD95 which in turn anchors NMDARs and AMPARs. The extracellular domain contains the Neurexin binding site. Nlgns have four isoforms (1-4), with Nlgn1 present at excitatory synapses. Previous slice electrophysiological study in the CA1 of Nlgn1 and Nlgn123 cKO mice demonstrated that Nlgn1 or Nlgn123 deletion does not affect basal synaptic transmission but ablates LTP. These findings open up the crucial question of NL1’s mechanistic role in LTP. We identified the mechanisms of how Nlgn1, regulates long-term potentiation and basal synaptic transmission. Although neuroligins are extensively studied, due to their link to neuropsychiatric disorders, there are still a number of controversies concerning their functions, considering the differences and limitations in techniques applied. One of the major cofounds arises from the fact that neuroligins can heterodimerize. In order to unequivocally address the function of neuroligin-1 in synaptic plasticity, I used a mouse model where all Nlgns 1-4 are conditionally deleted and replaced with rescue mutants. These experiments uncovered a surprising disparity in Nlgn1’s role in regulating basal transmission versus long-term potentiation. While NMDAR-dependent LTP is mediated by binding of Nlgn1 to presynaptic β-neurexins, but not the cytoplasmic sequences of Nlgn1, basal NMDAR-mediated responses involve a neurexin-independent mechanism that requires the Nlgn1 cytoplasmic tail. These findings demonstrate that Nlgn1 performs two mechanistically distinct functions and that Nlgn1 mediated trans-synaptic cell adhesion signaling critically regulates LTP. These results significantly advance our understanding of molecular mechanisms governing a prototypic form of synaptic plasticity and also provide a molecular framework, which will be valuable for identifying potential therapeutic targets for debilitating common mental disorders.
Publications
- Neuroligin-1 Signaling Controls LTP and NMDA Receptors by Distinct Molecular Pathways. Neuron. 2019 May 8;102(3):621-635.e3
Wu X, Morishita WK, Riley AM, Hale WD, Südhof TC, Malenka RC
(See online at https://doi.org/10.1016/j.neuron.2019.02.013)
