PSD-95-like membrane associated guanylate kinases (PSD-MAGUKs) and synaptic plasticity
Highlights
► Role of PSD-95 in regulating synaptic plasticity. ► PSD-95 as the slot protein of AMPARs and as the signaling scaffold. ► Functional diversity of PSD-MAGUKs in synaptic plasticity.
Introduction
PSD-95-like membrane associated guanylate kinases (PSD-MAGUKs) constitute a major family of multidomain scaffold proteins at glutamatergic synapses, including PSD-95 (SAP90), PSD-93 (Chapsyn-110), SAP102, and SAP97. They are multi-modular proteins sharing the common domain structure of three PSD-95/Discs large/zona occludens-1 (PDZ) domains, followed by a Src-homology-3 (SH3) domain and a catalytically inactive guanylate kinase (GK) domain. They interact with a variety of membrane proteins including ionotropic glutamate receptors, ion channels, neuromodulatory receptors, and cell-adhesion molecules. PSD-MAGUKs also interact with intracellular proteins including other scaffold proteins, actin cytoskeleton components, and signaling proteins [1, 2, 3]. Among the family members, expression of PSD-95 and PSD-93 has been shown to be dysregulated in neuropsychiatric patients [4], and loss of function mutations in the SAP102 gene causes nonsyndromic X-linked mental retardation [5]. Furthermore, within the array of interaction partners, several were identified in genetic studies of neuropsychiatric and neurodevelopmental disorders, including neuroligins in autism spectrum disorder [6], SAPAP3 in obsessive compulsive disorder [7], and its interaction partner SHANK family proteins in autism spectrum disorders (ASD) [8, 9], poising PSD-MAGUKs a central role in orchestrating normal synaptic function at glutamatergic synapses. Here I focus on the recent studies exploring the possible roles of PSD-MAGUKs in synaptic plasticity, and discuss several prevalent hypotheses.
Section snippets
PSD-95 and synaptic plasticity
Among the four PSD-MAGUKs family members, PSD-95 is the most extensively studied one in the context of synaptic plasticity. It is highly enriched in the PSD [10] and has been proposed to play an essential role for maintaining and regulating synaptic AMPAR function [11••]. In vivo studies have shown that activity-dependent redistribution of PSD-95 in visual cortex correlates with eye opening [12], and is thought to be involved in the control of developmental plasticity [13]. PSD-mutant mice
NMDAR-dependent LTD, and the slot hypothesis of PSD-95
It has been hypothesized that PSD-95 may act as a ‘slot’ protein for synaptic AMPARs with the concentration of PSD-95 at the synapse regulating synaptic AMPAR levels [23, 24•]. A signaling cascade initiated by an LTD-inducing stimulus is hypothesized to lead to the removal of synaptic PSD-95 and consequently synaptic AMPARs. Data supporting this scenario first came from studies of agonist-induced AMPAR endocytosis in dissociated neuron culture. It has been reported that synaptic PSD-95 levels
NMDAR-dependent LTD, and the signaling scaffold hypothesis of PSD-95
As a multi-modular protein, PSD-MAGUKs interact with an array of intracellular proteins that have been implicated in synaptic plasticity. Studies on PSD-95 mutant mice suggested that PSD-95 is essential for mediating LTD. Using a molecular replacement strategy, studies have shown that the effects of PSD-95 on regulating basal synaptic AMPAR function and mediating LTD can be dissociated [19••]. The SH3-GK domain of PSD-95, which interacts with AKAP79/150, is suggested to be critical for the
NMDAR-dependent LTP
Data from PSD-95 mutant animals and overexpression studies suggest that PSD-95 is a negative regulator of NMDAR-dependent LTP [14•, 21]. Acute knockdown studies showed that the induction of synaptic LTP is not affected by the lack of PSD-95, whereas spine growth (structural plasticity) is impaired [20, 29•], suggesting different contributions of PSD-95 in regulating structural and functional LTP. It has been shown that S295 of PSD-95 can be dephosphorylated with the chemLTP protocol [27•], but
Plasticity of NMDARs
Recent studies suggest that PSD-95 is involved in muscarinic acetylcholine receptors (mAChRs)-induced LTD of NMDAR mediated synaptic transmission [34]. Knocking down PSD-95 and replacement with PSD-95 mutants lacking the SH3 domain blocked mAchR agonist-induced LTD of NMDAR EPSCs due to the disruption of interaction with hippocalcin. This effect can also be dissociated from the effects of PSD-95 on AMPAR and NMDAR EPSCs. Thus, several lines of evidence showed that effects of PSD-95 on basal
Homeostatic plasticity
Homeostatic plasticity acts to stabilize neuronal activity upon perturbations [35]. In the dissociated neuronal culture system, when synaptic activity is chronically blocked with TTX, synaptic AMPAR responses are elevated to compensate for the lack of activity; whereas when neuronal activity is chronically elevated with GABAR blocker bicuculline, synaptic AMPAR responses are decreased. This experimental observation, named as synaptic scaling, has been used as a model for homeostatic plasticity.
Other PSD-MAGUKs and plasticity
Evidence of the involvement of PSD-MAGUKs in synaptic plasticity first came from studies on genetically mutated animals. Among four family members, genetic deletions of PSD-95, PSD-93, and SAP102 have all shown deficits in a variety of Hebbian type synaptic plasticity [14•, 38•, 18••]. SAP97-null animals are embryonic lethal, and studies on conditional knockout have not shown a deficit in an NMDAR-dependent LTP paradigm [39]. Table 1 compares the outcome in plasticity from PSD-MAGUK mutant
PSD-93
Previous studies suggest that the role of PSD-95 and PSD-93 in regulating basal synaptic AMPAR function is overlapping [11••]. The expression profiles throughout development are similar as well. In rodents, PSD-95 and PSD-93 express at low level early during development, and start to increase the expression from postnatal 10 days until they reach high levels in the adulthood (six months) [40]. Although the phenotypes on basal transmission by regulating either PSD-95 or PSD-93 levels are
SAP97
The predominant SAP97 isoform contains an L27 domain in the N-terminal region (β-isoform), which differs from the predominant PSD-95 isoform that has a palmitoylation signal in the N-terminal region (α-isoform) [42, 43•]. Unlike PSD-95, which interacts with AMPARs through direct binding to the transmembrane AMPAR regulatory proteins (TARPs) [23, 44], SAP97 binds directly the AMPAR subunit GluR1 [45, 46]. Studies on basal transmission showed that overexpression of SAP97 has little effect on
SAP102
SAP102 is expressed early during development, and its expression stays stable throughout adulthood [40]. In comparison, the expression of PSD-95 starts from postnatal day 10 and increases throughout development until adulthood. Compared to PSD-95, SAP102 has an unstructured N-terminal region. In mature neurons, SAP102 is highly mobile compared to PSD-95 [47]. During development, PSD-95 becomes enriched in the PSD [40]. Consistent with this observation, manipulating SAP102 in relatively mature
Conclusion
The role of PSD-95 in regulating synaptic AMPAR functions has been established with overwhelming evidence. In this review, I have summarized the recent studies supporting that PSD-95 not only forms structural scaffold for anchoring AMPARs at the PSD, but also serves as the signaling scaffold to bridge NMDARs to the intracellular signaling complexes. The role of PSD-95 in basal synaptic AMPAR function can be separated from its role in synaptic plasticity. Furthermore, the dynamics of PSD-95 is
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
I apologize, due to the space limitation; many excellent publications could not be cited. I thank Oliver Schluter and Xu lab members including Patrick Redman, Kendrick Jones, and Mingna Liu for helpful comments. This work is supported by the grant from the National Institute of Mental Health (MH080310).
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