Roles of palmitoylation in structural long-term synaptic plasticity

Abstract

Long-term potentiation (LTP) and long-term depression (LTD) are important cellular mechanisms underlying learning and memory processes. N-Methyl-D-aspartate receptor (NMDAR)-dependent LTP and LTD play especially crucial roles in these functions, and their expression depends on changes in the number and single channel conductance of the major ionotropic glutamate receptor α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) located on the postsynaptic membrane. Structural changes in dendritic spines comprise the morphological platform and support for molecular changes in the execution of synaptic plasticity and memory storage. At the molecular level, spine morphology is directly determined by actin cytoskeleton organization within the spine and indirectly stabilized and consolidated by scaffold proteins at the spine head. Palmitoylation, as a uniquely reversible lipid modification with the ability to regulate protein membrane localization and trafficking, plays significant roles in the structural and functional regulation of LTP and LTD. Altered structural plasticity of dendritic spines is also considered a hallmark of neurodevelopmental disorders, while genetic evidence strongly links abnormal brain function to impaired palmitoylation. Numerous studies have indicated that palmitoylation contributes to morphological spine modifications. In this review, we have gathered data showing that the regulatory proteins that modulate the actin network and scaffold proteins related to AMPAR-mediated neurotransmission also undergo palmitoylation and play roles in modifying spine architecture during structural plasticity.

Keywords: AMPAR; Actin cytoskeleton; Lipid posttranslational modification; Long term depression (LTD); Long term potentiation (LTP); Rho GTPases; Structural plasticity.

Fig. 1

Spine enlargement in LTP and shrinkage in LTD. LTP triggers spine enlargement (the transient, fast increase to ~ 200 to 400% of spine head volume at 1–5 min, followed by ~ 50% increase persisting for over 1 h), which is supported by an increased actin cytoskeleton network within the spine [–22]. Meanwhile, more AMPARs are recruited to the postsynaptic membrane through exocytosis and anchored on the postsynaptic density (PSD), which is also increased in the persistent phase of LTP. Conversely, LTD induces AMPAR endocytosis and spine shrinkage (a decrease by ~ 30% of spine head volume at 45 min after low-frequency stimulation) with depolymerization of the actin cytoskeleton network [18, 22, 23]

Fig. 2

AMPAR and its associated scaffold proteins whose palmitoylation contributes to the modulation of spine morphology. The figure shows that several associated scaffold proteins of the AMPAR GluA1/2 and GluA2/3 heterotetramers (the major combinations of functional AMPARs in nervous system) undergo palmitoylation in the postsynaptic side of the excitatory synapses to regulate AMPAR membrane trafficking and postsynaptic architecture. Noteworthy, Ankyrin-G was shown to partially colocalize with GluA1 puncta perisynaptically in the spine head but the interaction between Ankyrin-G and GluA1 seems to be indirect and could be mediated by multiple proteins [244]. Palmitoylation of these proteins appears to play important roles in regulating their membrane localization and affects AMPAR trafficking on the postsynaptic membrane. It also contributes to spine structure modulation through various signaling pathways, which are described in this chapter. TARP: transmembrane AMPA receptor regulatory protein. One squiggle denotes one or more palmitoyl chains attached to the targeted protein. PSD-95 line icon denotes several PSD-95 molecules

Fig. 3

PSD-95 protein interactions are interrupted by Ca²⁺ influx which affects also PSD-95 relation with actin networks. A. PSD-95 is anchored on the postsynaptic membrane via palmitoylation at Cys3 and Cys5 and α-actinin anchoring. Through binding the N-terminus of palmitoylated PSD-95, CDKL5 is targeted to postsynaptic sites where it forms a complex with Rac1 to regulate the actin cytoskeleton via the Rac1 signaling pathway. B. Upon activity-induced Ca²⁺ influx through NMDAR, activated calmodulin (CaM), due to Ca²⁺ binding, caps the N-terminal of PSD-95, leading to blocked accessibility of palmitoylation sites and binding sites for CDKL5 and α-actinin. This process results in downregulation of PSD-95 palmitoylation and release of PSD-95 from the postsynaptic membrane. As a result, CDKL5 will also be released from the synapses and fail to form complexes with Rac1. Illustration based on [, –278]. One squiggle denotes one palmitoyl chain attached to PSD-95

Fig. 4

The Ankyrin-G isoforms highly expressed in neurons and localization of palmitoylation site in conserved membrane-binding domain. Ankyrin-G contains: membrane-binding domain, spectrin-binding domain and the death domain/C terminal regulatory domain. In addition to these three domains, Ankyrin-G 480-kDa and Ankyrin-G 270-kDa contain an extra spliced exon, a longer one and a shorter one, respectively. The palmitoylation site is a single conserved cysteine located in a loop of the first ankyrin repeat of its membrane binding domain [106, 281]

Fig. 5

Roles of palmitoylation during structural LTP. During LTP, more AMPARs are recruited to the postsynaptic membrane via exocytosis and anchored on an enlarged PSD and on Ankyrin-G, which more densely populate the submembrane region than in the basal state. Ankyrin-G molecules are targeted to perisynaptic sites of the spine head and spine neck to stabilize the spine structure through palmitoylation and binding to spectrin (1:1), which is a cytoskeletal protein that lines the intracellular side of the plasma membrane interacting with actin cytoskeletal protein. AMPAR, 4.1 N, spectrin, actin and associated molecules form a membrane-associated periodic skeleton (MPS) structure observed in spines, but the extent to which it exists and how it develops in dendrites remain unclear [340, 341]. Palmitoylation targets Rac1, Cdc42, Ras and LIMK1 to spine membrane where Rac1 and Cdc42 activate PAK. Next, phosphorylated LIMK1 by activated PAK phosphorylates Cofilin and inhibits its depolymerizing activity. Palmitoylated Ras seems to participate in spine morphological modification through downstream MEK/ERK signaling pathway. In addition, through downstream WAVE and WASP, Rac1 and Cdc42 also regulate Arp2/3-mediated actin polymerization, which can be inhibited by PICK1. Palmitoylation also seems to facilitate assembly of the complex containing AMPAR, ABP-L, N-cadherin and δ-catenin on the postsynaptic membrane, linking AMPAR trafficking to the actin cytoskeleton network through Rho signaling. Regulation of functional and structural plasticity is a highly sophisticated process which needs precise timing of coordinated work of plenty of factors. Interplay between the processes described above and other, unknown factors, may lead to enhanced synaptic transmission and enlarged spines. The sketch was prepared based on the data collected in this review. One squiggle denotes one or more palmitoyl chains attached to the target protein; Spectrin line icon denotes several spectrin molecules