TY - JOUR
T1 - Activity-Dependent Validation of Excitatory versus Inhibitory Synapses by Neuroligin-1 versus Neuroligin-2
AU - Chubykin, Alexander A.
AU - Atasoy, Deniz
AU - Etherton, Mark R.
AU - Brose, Nils
AU - Kavalali, Ege T.
AU - Gibson, Jay R.
AU - Südhof, Thomas C.
N1 - Funding Information:
We would like to thank Dr. Y. Goda (University College London) and Dr. Antony A. Boucard (UT Southwestern, Dallas) for expression vectors. This study was supported by a grant from the NIMH (R37 MH52804-08 to T.C.S.). E.T.K. is an Established Investigator of the American Heart Association.
PY - 2007/6/21
Y1 - 2007/6/21
N2 - 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.
AB - 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.
KW - MOLNEURO
KW - SIGNALING
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U2 - 10.1016/j.neuron.2007.05.029
DO - 10.1016/j.neuron.2007.05.029
M3 - Article
C2 - 17582332
AN - SCOPUS:34250211762
SN - 0896-6273
VL - 54
SP - 919
EP - 931
JO - Neuron
JF - Neuron
IS - 6
ER -