Bidirectional signaling by cell-adhesion molecules is thought to mediate synapse formation, but the mechanisms involved remain elusive. Here we found that the adhesion-G-protein-coupled receptors latrophilin-2 and latrophilin-3 selectively directed formation of perforant-path and Schaffer-collateral synapses, respectively, to hippocampal CA1-region neurons. Latrophilin-3 binds to two trans-cellular ligands, fibronectin leucine-rich-repeat transmembrane proteins (FLRTs) and teneurins. In vivo, both binding activities were required for input-specific synapse formation, suggesting that coincident binding of both ligands is necessary for synapse formation. In vitro, teneurin or FLRT alone did not induce excitatory synapse formation, whereas together they potently did so. Thus, postsynaptic latrophilins promote excitatory synapse formation by simultaneous binding of two unrelated presynaptic ligands, which is required for formation of synaptic inputs at specific dendritic localizations. INTRODUCTION: In brain, synaptic connections form neuronal communication networks, thereby constructing neural circuits. Synaptic connections are exquisitely specific and dynamic, but the underlying molecular mechanisms remain largely unexplored. In the hippocampus, Schaffer-collateral axons from the CA3 region form synapses on CA1 region pyramidal neurons exclusively on dendritic domains in the S. oriens and S. radiatum of these neurons. In contrast, perforant-path axons from the entorhinal cortex form synapses on CA1 region pyramidal neurons exclusively on dendritic domains in the S. lacunosum-moleculare. How this synaptic input specificity is achieved, however, and what signaling mechanisms maintain the two classes of synapses, is unknown. RATIONALE: Synapse formation is thought to involve bidirectional signaling by trans-synaptic cell-adhesion molecules. Building on recent observations that the adhesion G-protein coupled receptor (GPCR) latrophilin-2 is essential for synapses in the S. lacunosum-moleculare of the CA1 region, we asked whether distinct latrophilins are localized to different dendritic domains of CA1 region neurons. Moreover, latrophilins are known to form trans-cellular interactions with two classes of cell-adhesion molecules, teneurins and fibronectin leucine-rich-repeat transmembrane proteins (FLRTs). Thus we hypothesized that latrophilins may act in synapse formation via trans-synaptic interactions with these adhesion molecules as ligands, and that such interactions may contribute to the specificity of synapse formation. RESULTS: We produced genetic manipulations that allow monitoring the localization of endogenous latrophilin-2 and latrophilin-3 in vivo and that enable their conditional deletion. Using these manipulations, we found that latrophilin-2 and latrophilin-3 were specifically localized to postsynaptic spines in non-overlapping dendritic domains of CA1 region pyramidal neurons. Latrophilin-2 was targeted only to excitatory synapses in the S. lacunosum-moleculare, whereas latrophilin-3 was targeted o...

SUMMARY Neuronal activity influences genes involved in circuit development and information processing. However, the molecular basis of this process remains poorly understood. We found that HDAC4, a histone deacetylase that shuttles between the nucleus and cytoplasm, controls a transcriptional program essential for synaptic plasticity and memory. The nuclear import of HDAC4 and its association with chromatin is negatively regulated by NMDA receptors. In the nucleus, HDAC4 represses genes encoding constituents of central synapses, thereby affecting synaptic architecture and strength. Furthermore, we show that a truncated form of HDAC4 encoded by an allele associated with mental retardation is a gain-of-function nuclear repressor that abolishes transcription and synaptic transmission despite the loss of the deacetylase domain. Accordingly, mice carrying a mutant that mimics this allele exhibit deficits in neurotransmission and spatial memory. These studies elucidate a mechanism of experience-dependent plasticity and define the biological role of HDAC4 in the brain.

Teneurins (TENs) are cell-surface adhesion proteins with critical roles in tissue development and axon guidance. Here, we report the 3.1-Å cryoelectron microscopy structure of the human TEN2 extracellular region (ECR), revealing a striking similarity to bacterial Tc-toxins. The ECR includes a large β barrel that partially encapsulates a C-terminal domain, which emerges to the solvent through an opening in the mid-barrel region. An immunoglobulin (Ig)-like domain seals the bottom of the barrel while a β propeller is attached in a perpendicular orientation. We further show that an alternatively spliced region within the β propeller acts as a switch to regulate trans-cellular adhesion of TEN2 to latrophilin (LPHN), a transmembrane receptor known to mediate critical functions in the central nervous system. One splice variant activates trans-cellular signaling in a LPHN-dependent manner, whereas the other induces inhibitory postsynaptic differentiation. These results highlight the unusual structural organization of TENs giving rise to their multifarious functions.