EXPRESSION OF NEOCORTICAL SPIKE TIMING-DEPENDENT LONG-TERM DEPRESSION BY MODULATION OF PRESYNAPTIC NMDA RECEPTOR TONE

Spike timing-dependent long-term depression (tLTD) in the barrel cortex at the L4-L2/3 synapse in the first weeks of life has previously been shown to be dependent upon the action of presynaptic NMDA receptors, being blocked by both the presynaptic inclusion of the NMDA receptor pore-blocker MK-801 and by a layer 4 GluN1 knockout. It is now shown that 7-chlorokynurenic acid (7-CK), an antagonist at the NMDA receptor glycine binding site, mediates a rundown in synaptic activity which is, like tLTD, expressed as a reduction in transmitter release probability and is not dependent upon presynaptic activity or the GluN2 subunit, being insensitive to the glutamate binding site antagonist AP5. The action of 7-CK is blocked by a presynaptic GluN1 knockout. 7-CK-induced depression and tLTD are also shown to mutually occlude one another in an input-specific manner, whilst the addition of D-serine, the physiological co-agonist of the NMDA receptor at the glycine binding site, rescues synaptic activity back to baseline after the induction of tLTD. 7-CK also occludes the induction of spike pattern-dependent LTD, a form of plasticity which is mediated presynaptically and is independent of postsynaptic and astroglial elements. These findings suggest a role for non-conventional NMDA receptors which are tonically activated, possibly by astroglial co-agonist release, with a reduction in their activity perhaps mediating the expression of spike timing-dependent long-term depression. The pharmacology of this effect suggests that NMDA receptors responsible may be of the GluN2-lacking, GluN1-GluN3 excitatory glycine receptor type.