Dendritic spine formation and synaptic function require neurobeachin

Abstract

A challenge in neuroscience is to understand the mechanisms underlying synapse formation. Most excitatory synapses in the brain are built on spines, which are actin-rich protrusions from dendrites. Spines are a major substrate of brain plasticity, and spine pathologies are observed in various mental illnesses. Here we investigate the role of neurobeachin (Nbea), a multidomain protein previously linked to cases of autism, in synaptogenesis. We show that deletion of Nbea leads to reduced numbers of spinous synapses in cultured neurons from complete knockouts and in cortical tissue from heterozygous mice, accompanied by altered miniature postsynaptic currents. In addition, excitatory synapses terminate mostly at dendritic shafts instead of spine heads in Nbea mutants, and actin becomes less enriched synaptically. As actin and synaptopodin, a spine-associated protein with actin-bundling activity, accumulate ectopically near the Golgi apparatus of mutant neurons, a role emerges for Nbea in trafficking important cargo to pre- and postsynaptic compartments.

Neurobeachin regulates neurotransmitter receptor trafficking to synapses

“…The effects on docked SVs and SV cluster size in Nbea KO cells that we observed might be a secondary effect of the chronically altered synaptic transmission in mutant neurons. Such structural changes occur upon chronic changes in activity and are in accord with other ultrastructural changes that were observed in the Nbea KO brain (Niesmann et al, 2011).…”

“…Defects in synapse morphology, enrichment of synaptic molecules, and synaptic transmission were described in two Nbea knockout (KO) mouse lines (Su et al, 2004;Medrihan et al, 2009;Niesmann et al, 2011). We now demonstrate that defects in the synaptic localization of ionotropic receptors for the key excitatory and inhibitory neurotransmitters are a major cause of these defects and that, in the absence of Nbea, these receptors accumulate in the biosynthetic pathway.…”

Drosophila rugoseIs a Functional Homolog of MammalianNeurobeachinand Affects Synaptic Architecture, Brain Morphology, and Associative Learning

“…Nbea mainly localizes to endomembranes near the TGN, consistent with a possible function for Nbea upstream in a secretory pathway (Wang et al, 2000). A function for Nbea in trafficking is further suggested by the accumulation of actin and synaptopodin, a spine-associated protein with actin-bundling activity, near the Golgi of Nbea Ϫ/Ϫ neurons (Niesmann et al, 2011). In Drosophila, spine-like structures are abundant at lobular plate tangential cells of the visual system, thus directly providing a putative fly model for this aspect of Nbea/rg function.…”

“…NBEA is a multidomain scaffolding protein with an AKAP (A-kinase anchor protein) domain and is localized near the transGolgi network (TGN) (Wang et al, 2000), supporting a function in vesicle sorting or secretion as demonstrated by experiments performed in Nbea knock-out mice and in vitro (Wang et al, 2000;Su et al, 2004;Medrihan et al, 2009;Castermans et al, 2010;Niesmann et al, 2011). Whereas NBEA is known for its neuronal function and its implication in autism spectrum disorders (Castermans et al, 2003;Volders et al, 2011), the human homolog LRBA has a broad expression pattern, and its function is currently unknown (Wang et al, 2001).…”

Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex

“…The E3 ubiquitin ligase Ube3A, linked to Angelman syndrome, also controls spine formation 3 . Moreover, another autism-related protein neurobeachin regulates spine density and shaft synapse formation 4 . Thus, childhood mental disorders may be accompanied by morphological abnormalities of excitatory spine and/or shaft synapses.…”