Presynaptic NMDA receptors, cannabinoid release and LTD induction in layer 5 cells

It is widely accepted that postsynaptic NMDA receptors (NMDARs) detect coincident pre- and postsynaptic activity during the induction of timing-dependent long-term potentiation (tLTP). Less is known, however, about the mechanisms that underlie timing-dependent long-term depression (tLTD). Although induction of tLTD is known to depend on activation of NMDARs, the factors determining the temporal window for tLTD remain elusive. We set out to investigate tLTD in connected pairs of visual cortical thick-tufted layer-5 (L5) neurons.

We find that L5 tLTD changes short-term depression and the coefficient of variation consistent with presynaptic expression. The need for postsynaptic activity and the presynaptic expression imply retrograde signalling. Synthetic and endogenous agonists of the cannabinoid CB1 receptor produce depression that mimics and occludes tLTD, suggesting that the retrograde signal is an endocannabinoid. Just like tLTD, CB1 agonist-induced LTD requires presynaptic activity and NMDAR activation, but (as opposed to tLTD) it does not rely on postsynaptic Ca2+ influx.

LTD is produced only if the presynaptic neuron is active when endocannabinoid is bound to CB1 receptors. This presynaptic activity dependence relies on presynaptic NMDA autoreceptors that detect the release of glutamate. These presynaptic NMDARs are NR2B subunit-containing at an age when postsynaptic NMDARs are not. In agreement, tLTD, but not tLTP, is abolished by the NR2B-specific blocker ifenprodil.

Since LTD requires the presence of endocannabinoid, reduced rates of endocannbinoid breakdown may extend the tLTD temporal window. In agreement, blockers of endocannabinoid hydrolysis significantly increase the tLTD timing window.

In conclusion, tLTD requires simultaneous activation of presynaptic NMDA and CB1 receptors. This novel form of presynaptic coincidence detection may explain the temporal window of tLTD and may also impart synapse specificity to cannabinoid retrograde signaling.