Postsynaptic N-methyl-D-aspartate receptor function requires alpha-neurexins.
Alpha-neurexins are neuron-specific cell-surface molecules that are essential for the functional organization of presynaptic Ca2+ channels and release sites. We have now examined postsynaptic glutamate receptor function in alpha-neurexin knockout (KO) mice by using whole-cell recordings in cultured neocortical slices. Unexpectedly, we find that alpha-neurexins are required for normal activity of N-methyl-D-aspartate (NMDA)- but not alpha-amino-3-hydroxy-5-methyl-4-isoxyzolepropionic acid (AMPA)-type glutamate receptors. In alpha-neurexin-deficient mice, the ratio of NMDA- to AMPA-receptor currents, recorded as evoked synaptic responses, was diminished approximately 50%. Furthermore, the NMDA-receptor-dependent component of spontaneous synaptic miniature responses was reduced approximately 50%, whereas the AMPA-receptor-dependent component was unaffected. No alterations in the levels of NMDA- or AMPA-receptor proteins were detected. These results suggest that alpha-neurexins are required to maintain normal postsynaptic NMDA-receptor function. The decrease in NMDA-receptor activity in alpha-neurexin-deficient synapses could be due to a transsynaptic effect on the postsynaptic neuron (i.e., alpha-neurexins on the presynaptic inputs guide postsynaptic NMDA-receptor function) or to a cell-autonomous postsynaptic effect of alpha-neurexins on NMDA-receptor activity. To distinguish between these two possibilities, we cocultured WT GFP-labeled neurons with neocortical slices from alpha-neurexin-deficient or control mice. No difference was found between WT neurons innervated by inputs that contained or lacked alpha-neurexins, indicating that the absence of presynaptic alpha-neurexins alone does not depress postsynaptic NMDA-receptor function. Our data suggest that, in addition to the previously described presynaptic impairments, loss of alpha-neurexins induces postsynaptic changes by a cell-autonomous mechanism.
Kattenstroth
Gunnar
G
Lehrstuhl für Zellphysiologie, Ruhr-Universität, D-44780 Bochum, Germany.
Tantalaki
Evangelia
E
Südhof
Thomas C
TC
Gottmann
Kurt
K
Missler
Markus
M
D000818:Animals; D018929:Cell Culture Techniques; D017353:Gene Deletion; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000494:pharmacology; D019579:Neocortex / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D018091:Receptors, AMPA / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C093175:neurexin II; C082354:neurexin IIIalpha; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid