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application of inhibitors of PLC and DAGL [42] and suggest that the involvement of AEA in
DSI. Further studies are required to determine the enzymes for the EC production and the
related signaling molecule involved in hippocampal EC mediated LTD.
(d) Amygdala
EC mediated LTD has been found at GABAergic inhibitory synapses within the
basolateral nucleus of the amygdala (BLA) [137]. This LTD of inhibitory inputs (LTD
i
) is
induced by low-frequency (1 Hz, 100 pulses) stimulation, and PPF evidence indicates that
expression of this form of plasticity involves a presynaptic decrease in neurotransmitter
release and required CB1 activation. A further study reported that induction of LTDi was
dependent on mGluR1 activation but not on postsynaptic Ca
2+
influx [10]. Pharmacological
experiments with inhibitors of PLC and DAGL suggested that AEA rather than 2-AG was
involved in LTDi. Consistent with this idea, LTDi was enhanced in mice lacking the FAAH
enzyme [10]. Although it is not clear how mGluR1 activation causes AEA production, the
authors suggested that adenylyl-cyclase and protein kinase A might be involved. The
amygdala is crucial for acquisition and storage of fear memory [119] and presumably also for
its extinction. CB1 knockout mice showed strongly impaired short-term and long-term
extinction in auditory fear-conditioning tests, with unaffected memory acquisition and
consolidation. Treatment of wild-type mice with CB1 receptor antagonist mimicked the
phenotype of CB1 knockout mice, suggesting that CB1 is required at the moment of fear
memory extinction [136]. Although, the mechanism needs to be elucidated, these studies
suggest that EC signaling is important for the induction, but not the expression, phase of
LTD. EC mediated LTDi in the amygdala may underlie this process. It is less clear how LTD-
inducing synaptic activity leads to production of ECs and the identity of the EC involved in
EC mediated LTD in the amygdala needs to be investigated.
(e) Cortex
CB1 receptors are present on glutamatergic terminals in the prefrontal cortex [90], and
activation of the CB1 receptor by agonists suppresses glutamate EPSCs in layer V slices of
rat cortex, evidently by acting at a presynaptic site [9]. Cannabinoids facilitates LTD, at
expense of LTP in slices of rodent prefrontal cortex [9, 13]. Conversely, blockade of CB1
receptors with the antagonist SR141716A led to an increased likelihood of observing LTP,
although LTD was not entirely absent. Therefore, the EC system may serve to promote LTD
in layer V neurons of the PFC, without being absolutely required for the LTD. It remains to
be determined whether natural balance between LTD and LTP in the PFC is regulated by ECs
and CB1 receptors. In corticostriatal slice cultures, mGluR5 activation induced 2-AG
formation through the PLC-DAGL cascade [105]and remains to be determined the extent to
which 2-AG acts as a retrograde messenger in cortex LTD.
(f) Neocortex
Neocortical synapses exhibit spike-timing-dependent plasticity, which is induced by pre-
and postsynaptic firings with a certain pre-to-post timing [50]. When presynaptic firing
repeatedly precedes postsynaptic firing by 0 to 20 ms, LTP is usually induced. By contrast,
when presynaptic firing follows postsynaptic firing with a delay up to 100 ms, LTD is
induced. This timing-dependent LTD at glutamatergic synapses (LTDe) in visual cortical
