Regulation of spine and synapse formation by activity-dependent intracellular signaling pathways
Section snippets
Regulation of spine and synapse formation by small GTPases (see Figure 1)
Mature mushroom-shaped spines are unique micro-compartments that autonomously regulate the electrical and biochemical responses to synaptic activity. It is widely accepted that spine morphology and synapse function, via anchoring of key PSD proteins, is modulated by the actin cytoskeleton that is regulated largely by small GTPases (reviewed in [3]). The family of small GTPases (RhoA, Rac1, and Cdc42) cycle between an active GTP-bound form, promoted by guanine nucleotide exchange factors (GEFs),
Cdc42
Although multiple functions for RhoA and Rac in regulation of synaptogenesis have been described, roles of Cdc42 are less characterized. For example, expression of constitutively active Cdc42 (V12 mutant) does not appear to affect spine morphology or density [27]. However, a recent study identified Cdc42 as a synaptic palmitoylated protein that is essential for synaptogenesis [29•]. A brain-specific splice variant of Cdc42 is palmitoylated, and glutamate stimulation of cultured neurons causes a
MicroRNAs modulate spine formation and morphology
It is well established that localized protein synthesis, often initiated by activity-dependent regulation of translation factors, from selected mRNAs that are transported into dendrites and spines are important in modulating synaptic plasticity [30]. Recently, another mode of activity-modulated translational regulation in neurons via microRNAs (miRs) has been identified. MiRs are non-coding transcripts of approximately 19–24 nucleotides that regulate protein synthesis, either by destabilizing
LTP induces spine expansion and AMPAR trafficking
Several forms of synaptic plasticity result in morphological alterations of synapses, both pre- and postsynaptically. Mechanisms regulating trafficking of AMARs during homeostatic synaptic scaling have recently been reviewed [38] and won’t be dealt with here. It is known that LTP-inducing stimuli result in an initial robust and transient expansion of dendritic spines followed by a smaller but sustained increase in spine volume [39]. To date, few studies have examined the molecular mechanisms
LTD and morphological plasticity of spines?
The accepted model to date has been that bidirectional alterations of synaptic strength occur in parallel with corresponding changes in spine geometry. This concept is supported by studies on LTP (see above), and previous studies indicated that LTD is accompanied by a shrinkage in dendritic spines [66, 67]. Whether changes in structural plasticity are necessary to adjust synaptic weights or vice versa, however, still remains an open question. Recently, two independent groups challenged this
Future directions
It is clear that signaling pathways that regulate the actin cytoskeleton via the small GTPases are major players in dictating spine morphology. In fact, several neuropathologies are associated with mutations in these proteins that lead to abnormal spine/synapse maturation. As described in this review, these signaling pathways act on multiple GEFs and GAPs to fine-tune the balance between opposing roles of Rac1 and RhoA. Furthermore, miRs have recently been found to be important regulators of
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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These authors contributed equally to this paper.