Activity-dependent validation of excitatory versus inhibitory synapses by neuroligin-1 versus neuroligin-2.
Neuroligins enhance synapse formation in vitro, but surprisingly are not required for the generation of synapses in vivo. We now show that in cultured neurons, neuroligin-1 overexpression increases excitatory, but not inhibitory, synaptic responses, and potentiates synaptic NMDAR/AMPAR ratios. In contrast, neuroligin-2 overexpression increases inhibitory, but not excitatory, synaptic responses. Accordingly, deletion of neuroligin-1 in knockout mice selectively decreases the NMDAR/AMPAR ratio, whereas deletion of neuroligin-2 selectively decreases inhibitory synaptic responses. Strikingly, chronic inhibition of NMDARs or CaM-Kinase II, which signals downstream of NMDARs, suppresses the synapse-boosting activity of neuroligin-1, whereas chronic inhibition of general synaptic activity suppresses the synapse-boosting activity of neuroligin-2. Taken together, these data indicate that neuroligins do not establish, but specify and validate, synapses via an activity-dependent mechanism, with different neuroligins acting on distinct types of synapses. This hypothesis reconciles the overexpression and knockout phenotypes and suggests that neuroligins contribute to the use-dependent formation of neural circuits.
Chubykin
Alexander A
AA
Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA.
Atasoy
Deniz
D
Etherton
Mark R
MR
Brose
Nils
N
Kavalali
Ege T
ET
Gibson
Jay R
JR
Südhof
Thomas C
TC
D000818:Animals; D000831:Animals, Newborn; D001596:Benzylamines / Q000494:pharmacology; D015816:Cell Adhesion Molecules, Neuronal; D002478:Cells, Cultured; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000502:physiology; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D008565:Membrane Proteins / Q000172:deficiency / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000502:physiology*; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D009474:Neurons / Q000166:cytology / Q000502:physiology; D018408:Patch-Clamp Techniques; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013569:Synapses / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D000096926:Benzenesulfonamides
D001596:Benzylamines; D015816:Cell Adhesion Molecules, Neuronal; D018691:Excitatory Amino Acid Antagonists; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D013449:Sulfonamides; C093438:neuroligin 1; C098003:neuroligin 2; C072105:KN 93; D000096926:Benzenesulfonamides