Neuroligins mediate excitatory and inhibitory synapse formation: involvement of PSD-95 and neurexin-1beta in neuroligin-induced synaptic specificity.
The balance between excitatory and inhibitory synapses is a tightly regulated process that requires differential recruitment of proteins that dictate the specificity of newly formed contacts. However, factors that control this process remain unidentified. Here we show that members of the neuroligin (NLG) family, including NLG1, NLG2, and NLG3, drive the formation of both excitatory and inhibitory presynaptic contacts. The enrichment of endogenous NLG1 at excitatory contacts and NLG2 at inhibitory synapses supports an important in vivo role for these proteins in the development of both types of contacts. Immunocytochemical and electrophysiological analysis showed that the effects on excitatory and inhibitory synapses can be blocked by treatment with a fusion protein containing the extracellular domain of neurexin-1beta. We also found that overexpression of PSD-95, a postsynaptic binding partner of NLGs, resulted in a shift in the distribution of NLG2 from inhibitory to excitatory synapses. These findings reveal a critical role for NLGs and their synaptic partners in controlling the number of inhibitory and excitatory synapses. Furthermore, relative levels of PSD-95 alter the ratio of excitatory to inhibitory synaptic contacts by sequestering members of the NLG family to excitatory synapses.
Levinson
Joshua N
JN
Department of Psychiatry, the Brain Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Chéry
Nadège
N
Huang
Kun
K
Wong
Tak Pan
TP
Gerrow
Kimberly
K
Kang
Rujun
R
Prange
Oliver
O
Wang
Yu Tian
YT
El-Husseini
Alaa
A
D000818:Animals; D015153:Blotting, Western; D015816:Cell Adhesion Molecules, Neuronal; D002478:Cells, Cultured; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D004594:Electrophysiology; D015723:Gene Library; D049452:Green Fluorescent Proteins / Q000378:metabolism; D051528:Guanylate Kinases; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D005810:Multigene Family; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D013569:Synapses / Q000378:metabolism*; D014162:Transfection
D015816:Cell Adhesion Molecules, Neuronal; D018076:DNA, Complementary; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; C093438:neuroligin 1; C033652:postsynaptic density proteins; D049452:Green Fluorescent Proteins; C086959:neurexin Ibeta; D051528:Guanylate Kinases