Proteins That Promote Filopodia Stability, but Not Number, Lead to More Axonal-Dendritic Contacts

Abstract

Dendritic filopodia are dynamic protrusions that are thought to play an active role in synaptogenesis and serve as precursors to spine synapses. However, this hypothesis is largely based on a temporal correlation between filopodia formation and synaptogenesis. We investigated the role of filopodia in synapse formation by contrasting the roles of molecules that affect filopodia elaboration and motility, versus those that impact synapse induction and maturation. We used a filopodia inducing motif that is found in GAP-43, as a molecular tool, and found this palmitoylated motif enhanced filopodia number and motility, but reduced the probability of forming a stable axon-dendrite contact. Conversely, expression of neuroligin-1 (NLG-1), a synapse inducing cell adhesion molecule, resulted in a decrease in filopodia motility, but an increase in the number of stable axonal contacts. Moreover, RNAi knockdown of NLG-1 reduced the number of presynaptic contacts formed. Postsynaptic scaffolding proteins such as Shank1b, a protein that induces the maturation of spine synapses, increased the rate at which filopodia transformed into spines by stabilization of the initial contact with axons. Taken together, these results suggest that increased filopodia stability and not density, may be the rate-limiting step for synapse formation.

Short-Term Recognition Memory Correlates with Regional CNS Expression of microRNA-138 in Mice

“…We would speculate that retaining higher levels of miR-138 would inhibit new protein synthesis and depalmitoylation in dendrites which may in-turn inhibit production of new dendritic spines. In our model, retaining short-term recognition memory may be a matter of synaptic stability and preservation of neuronal energy stores by reducing rates of protein turnover, a mechanism supported by evidence suggesting that the fillipodia stability, not density, promotes synapse formation (30). The results presented here justify future experiments with transgenic miR-138 and assessing hippocampal neurophysiology and memory function.…”

The Rare TXNRD1_v3 (“v3”) Splice Variant of Human Thioredoxin Reductase 1 Protein Is Targeted to Membrane Rafts by N-Acylation and Induces Filopodia Independently of Its Redox Active Site Integrity

“…Additionally, several studies link induction of filopodia to stimulation or patching of membrane raft microdomains (43, 60 -63). An example that is reminiscent of expression of v3(Grx) with induction of filopodia was given by Gauthier-Campbell and co-workers (61,62), studying phenotypes of Cos-7 cells as induced by expression of diverse palmitoylated peptides. In particular, a 14-amino acid doubly palmitoylated peptide derived from GAP43 (GAP-1-14) induced formation of filopodia when expressed in fusion with GFP (61,62).…”

“…An example that is reminiscent of expression of v3(Grx) with induction of filopodia was given by Gauthier-Campbell and co-workers (61,62), studying phenotypes of Cos-7 cells as induced by expression of diverse palmitoylated peptides. In particular, a 14-amino acid doubly palmitoylated peptide derived from GAP43 (GAP-1-14) induced formation of filopodia when expressed in fusion with GFP (61,62). Another example reminiscent of our findings herein is the neuronal glycoprotein M6a, which also associates with membrane rafts and induces formation of filopodia (63).…”

Pre- and Postsynaptic Assembly and Maturation

“…Changes in dendritic spine morphology are even thought to be the key regulator of memory formation and learning (Kasai et al, 2010). Dendritic spines contain all components essential for postsynaptic signaling and plasticity and therefore serve as good indicators of modifications in synaptic connectivity (Arstikaitis et al, 2011;Harms and Dunaevsky, 2007;Segal, 2005;Tada and Sheng, 2006;Yu and Zuo, 2011). Observation of changes in spine morphology and dynamic protein flux has been carried out intensely in the past years.…”