Postsynaptic N -methyl- d -aspartate receptor function requires α-neurexins

Abstract

␣-Neurexins are neuron-specific cell-surface molecules that are essential for the functional organization of presynaptic Ca 2؉ channels and release sites. We have now examined postsynaptic glutamate receptor function in ␣-neurexin knockout (KO) mice by using whole-cell recordings in cultured neocortical slices. Unexpectedly, we find that ␣-neurexins are required for normal activity of N-methyl-D-aspartate (NMDA)-but not ␣-amino-3-hydroxy-5-methyl-4-isoxyzolepropionic acid (AMPA)-type glutamate receptors. In ␣-neurexin-deficient mice, the ratio of NMDA-to AMPAreceptor currents, recorded as evoked synaptic responses, was diminished Ϸ50%. Furthermore, the NMDA-receptor-dependent component of spontaneous synaptic miniature responses was reduced Ϸ50%, 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 ␣-neurexins are required to maintain normal postsynaptic NMDAreceptor function. The decrease in NMDA-receptor activity in ␣-neurexin-deficient synapses could be due to a transsynaptic effect on the postsynaptic neuron (i.e., ␣-neurexins on the presynaptic inputs guide postsynaptic NMDA-receptor function) or to a cell-autonomous postsynaptic effect of ␣-neurexins on NMDAreceptor activity. To distinguish between these two possibilities, we cocultured WT GFP-labeled neurons with neocortical slices from ␣-neurexin-deficient or control mice. No difference was found between WT neurons innervated by inputs that contained or lacked ␣-neurexins, indicating that the absence of presynaptic ␣-neurexins alone does not depress postsynaptic NMDA-receptor function. Our data suggest that, in addition to the previously described presynaptic impairments, loss of ␣-neurexins induces postsynaptic changes by a cell-autonomous mechanism.T he physiological properties of excitatory synapses of a set of neurons, or even the same neuron, can differ remarkably (1-4). Multiple pre-and postsynaptic processes differentially regulate the strength of synapses. For example, in cortical synapses, the properties of presynaptic release sites formed by a single neuron can be differentially modulated by the postsynaptic target neuron (5). At least in part, this regulation appears to act on the amount of presynaptic Ca 2ϩ influx that is induced by an action potential. Conversely, postsynaptic glutamate receptors are modulated by synaptic activity (6, 7). Both of the two principal types of synaptic glutamate receptors, N-methyl-Daspartate (NMDA) and ␣-amino-3-hydroxy-5-methyl-4-isoxyzolepropionic acid (AMPA) receptors, undergo such usedependent changes (7-9). The two receptor types are coordinately up-or down-regulated when the total strength of the synaptic inputs into a neuron is held constant during synaptic scaling (9). In contrast, only AMPA receptors are selectively increased during NMDA-receptor-dependent long-term potentiation in the CA1 region of the hippocampus (7). Viewed together, synapses can thus be considered as dynamic units in wh...

Mouse neurexin-1α deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments

“…In support of this overall concept, ␣-neurexin triple KO mice exhibit major impairments in synaptic transmission that manifest largely, but not exclusively, as presynaptic changes (9)(10)(11)(12)(13). Importantly, ␣-neurexin KO mice do not display a major decrease in the number of excitatory synapses, and only a moderate decrease in inhibitory synapses (9,13).…”

Modulation of synaptic function through the α-neurexin–specific ligand neurexophilin-1

“…In fact, we reported previously that the GABA B R-mediated modulation of Ca V 2.2 channels, required for its effect on vesicle release (58), was also impaired at excitatory brainstem synapses of α-Nrxn KO mice (45). Even more importantly, α-Nrxn is abundantly expressed in glutamatergic neurons as well (12) and has unequivocal effects on release from excitatory synapses (9,44,46,78). These results cannot be explained by a simple association of α-Nrxn with inhibitory and, of β-Nrxn with excitatory terminals as cautioned before (37).…”

“…In addition, research has identified several molecules, mostly ion channels and receptors, which are functionally impaired when Nrxn expression is altered. Nrxn variants have been found to affect voltage-dependent calcium channels (9,10), GABA A R (7, 37), NMDAR (44), GABA B R (36,45), nicotinergic acetylcholine receptors (69), and AMPAR (47). These ionotropic and metabotropic receptors represent "target molecules" of Nrxn that may include some physical association, but it appears unlikely that the functional link to all these requires stable protein-protein interactions.…”

The complex genetics in autism spectrum disorders

“…Inactivation of the -form of all three Nrxns in mice impairs presynaptic neurotransmitter release, and postsynaptic receptor function [81][82][83]. KO of Nlgn-1, -2, and -3 in mice causes neonatal lethality, as well as massive synaptic alterations [80].…”