Synapse-specific Regulation of AMPA Receptor Function by PSD-95

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2006 Dec 7

PMID 17148601

Citations 216

Authors

Jean-Claude Beique

Da-Ting Lin

Myoung-Goo Kang

Hiro Aizawa

Kogo Takamiya

Richard L Huganir

Affiliations

Soon will be listed here.

Abstract

PSD-95 is a major protein found in virtually all mature excitatory glutamatergic synapses in the brain. Here, we have addressed the role of PSD-95 in controlling glutamatergic synapse function by generating and characterizing a PSD-95 KO mouse. We found that the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)subtype of glutamate receptor (AMPAR)-mediated synaptic transmission was reduced in these mice. Two-photon (2P) uncaging of MNI-glutamate onto individual spines suggested that the decrease in AMPAR function in the PSD-95 KO mouse stems from an increase in the proportion of "silent" synapses i.e., synapses containing N-methyl-d-aspartate (NMDA) receptors (NMDARs) but no AMPARs. Unexpectedly, the silent synapses in the KO mouse were located onto morphologically mature spines. We also observed that a significant population of synapses appeared unaffected by PSD-95 gene deletion, suggesting that the functional role of PSD-95 displays synapse-specificity. In addition, we report that the decay of NMDAR-mediated current was slower in KO mice: The contribution of NR2B subunit containing receptors to the NMDAR-mediated synaptic current was greater in KO mice. The greater occurrence of silent synapses might be related to the greater magnitude of potentiation after long-term potentiation induction observed in these mice. Together, these results suggest a synapse-specific role for PSD-95 in controlling synaptic function that is independent of spine morphology.

Citing Articles

Critical Role of Rho Guanine Nucleotide Exchange Factor 4 in Brain Function.

Kim H, Lee K, Yoo K, Kim J, Kim H, Lim C Mol Neurobiol. 2025; .

PMID: 39920439 DOI: 10.1007/s12035-025-04734-7.

An Updated Bio-Behavioral Profile of the Flinders Sensitive Line Rat: Reviewing the Findings of the Past Decade.

Steyn S Pharmacol Res Perspect. 2025; 13(1):e70058.

PMID: 39786312 PMC: 11717001. DOI: 10.1002/prp2.70058.

Mitigation of synaptic and memory impairments via F-actin stabilization in Alzheimer's disease.

P A H, Basavaraju N, Chandran M, Jaleel A, Bennett D, Kommaddi R Alzheimers Res Ther. 2024; 16(1):200.

PMID: 39244567 PMC: 11380428. DOI: 10.1186/s13195-024-01558-w.

MLKL-USP7-UBA52 signaling is indispensable for autophagy in brain through maintaining ubiquitin homeostasis.

Zhang Z, Chen S, Jun S, Xu X, Hong Y, Yang X Autophagy. 2024; 21(2):424-446.

PMID: 39193909 PMC: 11759533. DOI: 10.1080/15548627.2024.2395727.

Molecular mechanisms underlying sex and treatment-dependent differences in an animal model of cue-exposure therapy for cocaine relapse prevention.

Peterson L, Nguyen J, Ghani N, Rodriguez-Echemendia P, Qiao H, Guwn S Front Neurosci. 2024; 18:1425447.

PMID: 39176383 PMC: 11339646. DOI: 10.3389/fnins.2024.1425447.

References

Luthi A, Schwyzer L, Mateos J, Gahwiler B, McKinney R . NMDA receptor activation limits the number of synaptic connections during hippocampal development. Nat Neurosci. 2001; 4(11):1102-7. DOI: 10.1038/nn744. View

Sheng M, Wyszynski M . Ion channel targeting in neurons. Bioessays. 1997; 19(10):847-53. DOI: 10.1002/bies.950191004. View

Flint A, Maisch U, Weishaupt J, Kriegstein A, Monyer H . NR2A subunit expression shortens NMDA receptor synaptic currents in developing neocortex. J Neurosci. 1997; 17(7):2469-76. PMC: 6573498. View

Zhu J, Malinow R . Acute versus chronic NMDA receptor blockade and synaptic AMPA receptor delivery. Nat Neurosci. 2002; 5(6):513-4. DOI: 10.1038/nn0602-850. View

Liao D, Hessler N, Malinow R . Activation of postsynaptically silent synapses during pairing-induced LTP in CA1 region of hippocampal slice. Nature. 1995; 375(6530):400-4. DOI: 10.1038/375400a0. View

Kennedy M . The postsynaptic density at glutamatergic synapses. Trends Neurosci. 1997; 20(6):264-8. DOI: 10.1016/s0166-2236(96)01033-8. View

Turrigiano G, Nelson S . Homeostatic plasticity in the developing nervous system. Nat Rev Neurosci. 2004; 5(2):97-107. DOI: 10.1038/nrn1327. View

Malenka R, Nicoll R . Long-term potentiation--a decade of progress?. Science. 1999; 285(5435):1870-4. DOI: 10.1126/science.285.5435.1870. View

Migaud M, Charlesworth P, Dempster M, Webster L, Watabe A, Makhinson M . Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature. 1998; 396(6710):433-9. DOI: 10.1038/24790. View

10.

Stein V, House D, Bredt D, Nicoll R . Postsynaptic density-95 mimics and occludes hippocampal long-term potentiation and enhances long-term depression. J Neurosci. 2003; 23(13):5503-6. PMC: 6741246. View

11.

Matsuzaki M, Honkura N, Ellis-Davies G, Kasai H . Structural basis of long-term potentiation in single dendritic spines. Nature. 2004; 429(6993):761-6. PMC: 4158816. DOI: 10.1038/nature02617. View

12.

Berberich S, Punnakkal P, Jensen V, Pawlak V, Seeburg P, Hvalby O . Lack of NMDA receptor subtype selectivity for hippocampal long-term potentiation. J Neurosci. 2005; 25(29):6907-10. PMC: 6725356. DOI: 10.1523/JNEUROSCI.1905-05.2005. View

13.

Matsuzaki M, Nemoto T, Miyashita Y, Iino M, Kasai H . Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons. Nat Neurosci. 2001; 4(11):1086-92. PMC: 4229049. DOI: 10.1038/nn736. View

14.

Raastad M, Storm J, Andersen P . Putative Single Quantum and Single Fibre Excitatory Postsynaptic Currents Show Similar Amplitude Range and Variability in Rat Hippocampal Slices. Eur J Neurosci. 1992; 4(1):113-117. DOI: 10.1111/j.1460-9568.1992.tb00114.x. View

15.

Hsia A, Malenka R, Nicoll R . Development of excitatory circuitry in the hippocampus. J Neurophysiol. 1998; 79(4):2013-24. DOI: 10.1152/jn.1998.79.4.2013. View

16.

Bagal A, Kao J, Tang C, Thompson S . Long-term potentiation of exogenous glutamate responses at single dendritic spines. Proc Natl Acad Sci U S A. 2005; 102(40):14434-9. PMC: 1242281. DOI: 10.1073/pnas.0501956102. View

17.

Ehrlich I, Malinow R . Postsynaptic density 95 controls AMPA receptor incorporation during long-term potentiation and experience-driven synaptic plasticity. J Neurosci. 2004; 24(4):916-27. PMC: 6729816. DOI: 10.1523/JNEUROSCI.4733-03.2004. View

18.

Isaac J, Nicoll R, Malenka R . Evidence for silent synapses: implications for the expression of LTP. Neuron. 1995; 15(2):427-34. DOI: 10.1016/0896-6273(95)90046-2. View

19.

Liu L, Wong T, Pozza M, Lingenhoehl K, Wang Y, Sheng M . Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science. 2004; 304(5673):1021-4. DOI: 10.1126/science.1096615. View

20.

Massey P, Johnson B, Moult P, Auberson Y, Brown M, Molnar E . Differential roles of NR2A and NR2B-containing NMDA receptors in cortical long-term potentiation and long-term depression. J Neurosci. 2004; 24(36):7821-8. PMC: 6729941. DOI: 10.1523/JNEUROSCI.1697-04.2004. View