Regulation of spine and synapse formation by activity-dependent intracellular signaling pathways

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Formation of the human brain during embryonic and postnatal development is an extraordinarily complex process resulting at maturity in billions of neurons with trillions of specialized connections called synapses. These synapses, composed of a varicosity or bouton from a presynaptic neuron that communicates with a dendritic spine of the postsynaptic neuron, comprise the neural network that is essential for complex behavioral phenomena and cognition. Inappropriate synapse formation or structure is thought to underlie several developmental neuropathologies. Even in the mature CNS, alterations in synapse structure and function continues to be a very dynamic process that is foundational to learning and memory as well as other adaptive abilities of the brain. This synaptic plasticity in mature neurons, which is often triggered by certain patterns of neural activity, is again multifaceted and involves post-translational modifications (e.g. phosphorylation) and subcellular relocalization or trafficking (endocytosis/exocytosis) of existing synaptic proteins, initiation of protein synthesis from existing mRNAs localized in dendrites or spines, and triggering of new gene transcription in the nucleus. These various cellular processes support varying temporal components of synaptic plasticity that begin within 1–2 min but can persist for hours to days. This review will give a critical assessment of activity-dependent molecular modulations of synapses reported over the past couple years. Owing to space limitations, it will focus on mammalian excitatory (i.e. glutamatergic) synapses and will not consider several activity-independent signaling pathways (e.g. ephrinB receptor) that also modulate spine and synapse formation [1, 2].

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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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