Synaptic plasticity, a symphony in GEF

Abstract

Dendritic spines are the postsynaptic sites for the majority of excitatory synapses in the mammalian forebrain. While many spines display great stability, others change shape in a matter of seconds to minutes. These rapid alterations in dendritic spine number and size require tight control of the actin cytoskeleton, the main structural component of dendritic spines. The ability of neurons to alter spine number and size is essential for the expression of neuronal plasticity. Within spines, guanine nucleotide exchange factors (GEFs) act as critical regulators of the actin cytoskeleton by controlling the activity of Rho-GTPases. In this review we focus on the Rho-GEFs expressed in the nucleus accumbens and localized to the postsynaptic density, and thus positioned to effect rapid alterations in the structure of dendritic spines. We review literature that ties these GEFs to different receptor systems and intracellular signaling cascades and discuss the effects these interactions are likely to have on synaptic plasticity.

Figure 1

Rho-GEFs and Rho-GTPases expressed in the NAc and localized to the PSD. Gene diagrams are drawn to scale and represent SMART structures (http://smart.embl-heidelberg.de/) with several modifications (see Supplementary Table 2).

Figure 2

Rac-specific GEFs at the PSD: (a) Tiam1 with NR1 subunit of NMDA receptor, EphB, and TrkB; (b) Kalirin7 with PSD-95, PI-3-P/PI-3,5-P2, NR2B subunit of NMDA receptor, EphB, Cdk5, and AF-6/N-cadherin; (c) Arhgef7/β-Pix with CamKK/CamKI/PKA, GluR2/3 subunit of AMPA receptor via GIT1/liprin-α/GRIP, Pak, Shank, and EphB; (d) Rasgrf2 with Cdk5, NMDA, and AMPA receptors.

Figure 3

Rho/Cdc42-specific GEFs at the PSD: (a) Ngef/Ephexin1 with Pak, EphA4, Src, and Cdk5; (b) Arhgef2/Lfc/GEF-H1 with a microtubule, Spinophilin, GluR1 subunit of AMPA receptor, ERK1/2, AKAP121/PKA, and 14-3-3; (c) Arhgef9/Collybisitin with Gephyrin and Neuroligin-2; (d) Itsn1/Intersectin-L with N-WASP, EphB2, and Arp2/3.