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messengers in LTDe induction. It was found that LTDe was blocked by CB1 antagonist and
was absent in CB1-knockout mice, and suggesting that striatal LTDe was mediated by ECs
[74]. Further, postsynaptic loading with AEA transporter inhibitors prevented striatal LTDe,
suggesting the requirement of transporter-mediated release of AEA for LTDe induction [172].
Dopamine also modulated striatal EC release and LTDe induction in medium-spiny neurons
[116]. All these observations suggest that EC can act as a retrograde messenger in striatal
LTDe. The dorsal striatum is an important brain area for motor control and habit learning.
Because the striatum receives excitatory inputs from the cortex and thalamus, synaptic
plasticity of excitatory synapses in this area is thought to be crucial for such striatum-related
functions. The retrograde EC signaling might play a role in the striatal functions through the
contribution to LTDe. As for the molecular identity of EC for EC mediated -LTD, AEA and
2-AG appear to function in different brain regions. Although it is less clear how LTD-
inducing synaptic activity leads to production of AEA in the striatum, recent data suggest that
AEA mediate LTDe in the striatum [74, 172].
(b) Nucleus Accumbens
As in the striatum, EC-LTDe was observed in the nucleus accumbens (NAc)[170]. NAc-
LTDe was induced by prolonged, moderate frequency stimulation (10min at 13Hz) of
prelimbic cortical glutamatergic synapses. As in the striatal LTDe, NAc-LTDe was prevented
by CB1 receptor antagonists, enhanced by CB1 receptor agonists, and absent in CB1 receptor
knockout mice, indicating the involvement of EC signaling [170]. Importantly, once NAc
LTD was induced, the antagonist did not affect it, demonstrating that the LTD was not
maintained by a continual release of ECs, but rather represented a persistent effect of transient
CB1 receptor activation. The EC that mediated LTD was evidently released as a retrograde
messenger, because LTD was prevented by chelating postsynaptic Ca
2+
(with 20mM BAPTA)
in the recorded cell [170]. NAc-LTDe required both activation of mGluR5 and Ca
2+
release
from intracellular stores. Interestingly, in vivo exposure to Δ
9
-THC blocked NAc-LTDe,
which was explained by a functional tolerance of CB1 receptors [96, 138]. Because NAc is
crucial for behaviors related to motivation and reward, these results suggest that NAc- LTDe
might be related to addiction behavior. Synaptically triggered EC release in VTA
dopaminergic neurons was mainly driven by group I mGluR activation, was blocked by
inhibition of DAGL [143] suggesting the participation of 2-AG as a retrograde messenger in
NAc-LTDe.
(c) Hippocampus
It has been shown that CB1 receptor activation inhibits both LTP and LTD induction in
the hippocampus [184, 189]. EC-LTDi was also observed in the hippocampus [42]. Two
trains of high-frequency stimulation (100 Hz, 100 pulses) or theta burst stimulation in the
stratum radiatum of the CA1 region caused LTD at GABAergic inhibitory synapses. This
hippocampal LTDi was presynaptically expressed, blocked by CB1 antagonist [42] and
eliminated in CB1 knockout mice [43], suggesting the involvement of EC signaling. LTDi
was prevented by pharmacological blockade of mGluR1/5, PLC, and DAGL, but not by
postsynaptic loading of the Ca
2+
chelator BAPTA, suggesting that the generation of EC
through the mGluR1/5-PLCβ-DAGL pathway is required for LTDi induction. By examining
the effects of CB1 antagonist at different time periods before, during, and after LTDi, the
induction of LTDi was shown to require continuous activation of CB1 for 5 to 10 minutes.
