Postsynaptic density 95 controls AMPA receptor incorporation during long-term potentiation and experience-driven synaptic plasticity.
The regulated delivery of AMPA-type glutamate receptors (AMPARs) to synapses is an important mechanism underlying synaptic plasticity. Here, we ask whether the synaptic scaffolding protein PSD-95 (postsynaptic density 95) participates in AMPAR incorporation during two forms of synaptic plasticity. In hippocampal slice cultures, the expression of PSD-95-green fluorescent protein (PSD-95-GFP) increases AMPAR currents by selectively delivering glutamate receptor 1 (GluR1)-containing receptors to synapses, thus mimicking long-term potentiation (LTP). Mutational analysis shows that the N terminal of PSD-95 including the first two PDZ [PSD-95/Discs large (Dlg)/zona occludens-1 (ZO-1)] domains is necessary and sufficient to mediate this effect. Further supporting a role in synaptic plasticity, wild-type PSD-95 occludes LTP and dominant negative forms block LTP. Moreover, we demonstrate that PSD-95 also participates in AMPAR delivery during experience-driven plasticity in vivo. In the barrel cortex from experience-deprived animals, the expression of PSD-95-GFP selectively increases AMPAR currents, mimicking experience-driven plasticity. In nondeprived animals, PSD-95-GFP produces no additional potentiation, indicating common mechanisms between PSD-95-mediated potentiation and experience-driven synaptic strengthening. A dominant negative form of PSD-95 blocks experience-driven potentiation of synapses. Pharmacological analysis in slice cultures reveals that PSD-95 acts downstream of other signaling pathways involved in LTP. We conclude that PSD-95 controls activity-dependent AMPAR incorporation at synapses via PDZ interactions not only during LTP in vitro but also during experience-driven synaptic strengthening by natural stimuli in vivo.
Ehrlich
Ingrid
I
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Malinow
Roberto
R
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D015870:Gene Expression; D005799:Genes, Dominant; D049452:Green Fluorescent Proteins; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D017774:Long-Term Potentiation / Q000502:physiology*; D008164:Luminescent Proteins / Q000235:genetics; D008565:Membrane Proteins; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012683:Sensory Deprivation / Q000502:physiology; D013003:Somatosensory Cortex / Q000378:metabolism / Q000502:physiology; D013569:Synapses / Q000378:metabolism / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology; D014738:Vibrissae / Q000502:physiology
D000076122:Disks Large Homolog 4 Protein; D049452:Green Fluorescent Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D011993:Recombinant Fusion Proteins; C501449:Dlg4 protein, rat; C033652:postsynaptic density proteins; C104722:glutamate receptor ionotropic, AMPA 2