title: Soluble ICAM-5, a product of activity dependent proteolysis, increases mEPSC frequency and dendritic expression of GluA1.
abstract: Matrix metalloproteinases (MMPs) are zinc dependent endopeptidases that can be released from neurons in an activity dependent manner to play a role in varied forms of learning and memory. MMP inhibitors impair hippocampal long term potentiation (LTP), spatial memory, and behavioral correlates of drug addiction. Since MMPs are thought to influence LTP through a β1 integrin dependent mechanism, it has been suggested that these enzymes cleave specific substrates to generate integrin binding ligands. In previously published work, we have shown that neuronal activity stimulates rapid MMP dependent shedding of intercellular adhesion molecule-5 (ICAM-5), a synaptic adhesion molecule expressed on dendrites of the telencephalon. We have also shown that the ICAM-5 ectodomain can interact with β1 integrins to stimulate integrin dependent phosphorylation of cofilin, an event that occurs with dendritic spine maturation and LTP. In the current study, we investigate the potential for the ICAM-5 ectodomain to stimulate changes in α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR) dependent glutamatergic transmission. Single cell recordings show that the ICAM-5 ectodomain stimulates an increase in the frequency, but not the amplitude, of AMPA mini excitatory post synaptic currents (mEPSCs). With biotinylation and precipitation assays, we also show that the ICAM-5 ectodomain stimulates an increase in membrane levels of GluA1, but not GluA2, AMPAR subunits. In addition, we observe an ICAM-5 associated increase in GluA1 phosphorylation at serine 845. Concomitantly, ICAM-5 affects an increase in GluA1 surface staining along dendrites without affecting an increase in dendritic spine number. Together these data are consistent with the possibility that soluble ICAM-5 increases glutamatergic transmission and that post-synaptic changes, including increased phosphorylation and dendritic insertion of GluA1, could contribute. We suggest that future studies are warranted to determine whether ICAM-5 is one of a select group of synaptic CAMs whose shedding contributes to MMP dependent effects on learning and memory.
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC, United States of America.
authors.forename: Irina
authors.initials: I
authors.lastname: Lonskaya
authors.forename: John
authors.initials: J
authors.lastname: Partridge
authors.forename: Rupa R
authors.initials: RR
authors.lastname: Lalchandani
authors.forename: Andrew
authors.initials: A
authors.lastname: Chung
authors.forename: Taehee
authors.initials: T
authors.lastname: Lee
authors.forename: Stefano
authors.initials: S
authors.lastname: Vicini
authors.forename: Hyang-Sook
authors.initials: HS
authors.lastname: Hoe
authors.forename: Seung T
authors.initials: ST
authors.lastname: Lim
authors.forename: Katherine
authors.initials: K
authors.lastname: Conant
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology; D007150:Immunohistochemistry; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010766:Phosphorylation / Q000187:drug effects; D059748:Proteolysis; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D012995:Solubility
chemical_list: D015815:Cell Adhesion Molecules; D020782:Matrix Metalloproteinases; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D012694:Serine; C547413:ICAM5 protein, rat