Department of Biology and Volen Center for Complex Systems, 415 South Street, Waltham, MA 02454-9110

We examined the mechanism underlying spike timing-dependent LTD, using whole-cell recordings of synaptically connected, thick tufted layer-5 neurons in rat visual cortex.

Post-before-pre firing at frequencies ranging from 0.1 to 20 Hz reliably induced LTD (after/before=73.6±2.5%, n=68). The change in coefficient of variation (n=61) and short-term depression (n=21) indicated that LTD was due to reduced presynaptic release.

Since postsynaptic activation is required for spike timing-dependent LTD, there must be a retrograde messenger. The CB1 receptor antagonist AM251 abolished LTD induction (101±4.8%, n=11), suggesting that this messenger is an endocannabinoid. Consistent with this, anandamide (78.4±2.7%, n=4) and the CB1 receptor agonists ACEA (74.5±4.1%, n=19) produced LTD by reducing release. Furthermore, timing-based and anandamide-induced LTD occluded (76.7±7.8%, n=6, for simultaneous induction).

With ACEA, LTD was obtained only in the presence of presynaptic spiking (n=10). This activity dependence may ensure synapse specificity. AP-V abolished ACEA-induced LTD (119±18%, n=6), indicating that presynaptic NMDA receptors signal presynaptic activity. In agreement, postsynaptic BAPTA blocked LTD induction (109±7.4%, n=4), but not ACEA-mediated LTD (72.8±4.7%, n=4). In contrast, the broad spectrum mGluR antagonist LY341495 had no effect on ACEA-induced LTD (59.7±6.7%, n=6).

At timings normally outside the LTD window (-120 and -200 ms, 105±6.4%, n=11), LTD was obtained both with the anandamide transporter blocker AM404 (75.9±4.8%, n=5) and the fatty acid amide hydrolase antagonist AA-5-HT (77.4±5.0%, n=7). This suggests that the endocannabinoid may set the width of the LTD timing window.

(Funded by NIH.)

Keywords: STDP, ENDOCANNABINOID, NMDA RECEPTOR, SYNAPTIC PLASTICITY, SYNAPTIC TRANSMISSION