Abstract
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.