Liprin-α proteins are master regulators of human presynapse assembly

Abstract

Abstract Formation of mammalian synapses entails the precise alignment of presynaptic release sites with postsynaptic receptors but how nascent cell-cell contacts translate into assembly of presynaptic specializations remains unclear. Guided by pioneering work in invertebrates, we hypothesized that in mammalian synapsesLiprin-α proteins directly link trans-synapticinitial contacts to downstream steps. In human neurons lacking all four Liprin-α isoforms, nascent synaptic contacts are formed but the recruitment of active zone components and accumulation of synaptic vesicles is blocked, resulting in ‘empty’ boutons and loss of synaptic transmission. Interactions with presynaptic cell adhesion molecules (CAMs) of either the LAR-RPTP family or Neurexins via CASK are required to localize Liprin-α to nascent synaptic sites. Liprin-α subsequently recruits presynaptic components via a direct interaction with ELKS proteins. Thus, assembly of human presynaptic terminals is governed by a hierarchical sequence of events in which the recruitment of Liprin-α proteins by presynaptic CAMs is a critical initial step.