Biology Reference
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interneurons that are implicated in DSI express high levels of CB1 receptors, which are
localized to their axon terminals [108]. (d) Neuronal activity and Ca
2+
entry stimulate the
synthesis of 2-AG in hippocampal neurons and AEA and 2-AG in other neuronal cells [17,
19, 20]. Recently, DSI mediated by 2-AG was shown in the mouse substantia nigra pars
reticulate and rat cerebellum [192]. It remains to be established that EC-mediated DSI is
present in other brain regions such as the ventromedial medulla [203], amygdala [108], and
striatum [191], in which exogenously applied CB1 receptor agonists are known to suppress
IPSCs. These reports convincingly established that ECs are important mediators of short-term
plasticity.
The neurons in the hippocampus and cerebellum use ECs to carry out a signaling process
that is analogous in mechanism but opposite in sign to DSI, called depolarization-induced
suppression of excitation (DSE). Like DSI, DSE is induced by neuronal depolarization; it
consists of a transient depression in neurotransmitter release, and it requires a retrograde
endocannabinoid messenger. But unlike DSI, DSE targets glutamatergic rather than GABA
axon terminals and therefore it reduces the excitatory input to the affected cell [2, 164]. DSE
is mimicked and blocked by agonists and antagonists of CB1 receptors respectively [118,
127] and it is absent in the CB1 receptor knockout mouse [160].
CB1 receptor agonists
suppress EPSCs in other areas of the brain, evidently through presynaptic actions. For
instance, similar DSE was reported in the ventral tegamental area (VTA) as a Ca
2+
-dependent
phenomenon, blocked by both CB1 receptor antagonists AM281 and SR141716A
(rimonabant), and enhanced by WIN55212-2 [144]. Importantly, DSE was partially blocked
by the D
2
DA antagonist eticlopride and enhanced by the D
2
DA agonist quinpirole without
changing the presynaptic cannabinoid activity [144]. These observations indicate that
activation of D
2
DA receptors in the VTA significantly enhances the depolarization-induced
release of ECs, which are responsible for the inhibition of glutamate transmission in the VTA
[144]. The synchronous release of mEPSCs in Sr
2+
-substituted extracellular solution was
found to be reduced by ECs in the prefrontal cortex and striatum [9, 73]. Recently, it was
shown that 2-AG
is the retrograde messenger for train-induced suppression of
excitation at the
VTA-DA synapses [143]. It remains to be demonstrated whether or not DSE is present in the
striatum [73], substantia nigra [193], periaqueductal gray [202], and spinal cord [147].
(b) Receptor-Driven EC release
Another form of EC-mediated short-term plasticity, which is driven by receptor
activation was first discovered in the cerebellum [127]. Metabotropic glutamate receptors
(mGluRs) are G-protein-coupled receptors distributed throughout the CNS that modulate
multiple CNS functions, including neuronal excitability [4, 49] and neurotransmitter release
[37]. Recent data from several investigators have begun to uncover an entirely novel signaling
mechanism for mGluRs, namely the production and subsequent release of ECs.
Some of the effects (short- and long-term forms of synaptic plasticity) previously
attributed directly to mGluR activation are in fact indirectly mediated by signaling through
the EC system [65]. Recent studies suggest that mGluR/EC signaling is a widespread feature
of neuronal circuitry [65], given the widespread expression of postsynaptic group I mGluRs
throughout the CNS and a similar extensive expression of CB1 receptors. Activation of group
I mGluRs can cause the release of ECs in the cerebellum [127] and hippocampus [200].
