Biology Reference
In-Depth Information
(A) ECs-Mediated Short-Term Plasticity
The discovery of ECs such as AEA and 2-AG and the widespread localization of CB1
receptors in the brain have stimulated considerable excitement over the previously
unrecognized cannabinoid system and questions about the function of this ubiquitous network
in the nervous system. There is now overwhelming evidence that AEA and 2-AG interact
with CB1 receptors and share some of the biological properties of other cannabinoids, but
with significant differences. These significant differential effects involve other non-CB1
receptors and/or postulated CB3 receptors as described. In recent years, the functions of ECs
at the synaptic and network levels have been elucidated.
In 2001, three groups independently revealed that ECs are released when neuronal cells
(postsynaptic neurons and possibly presynaptic terminals as well) are activated. They travel in
a retrograde direction and transiently (<1 min) suppress presynaptic neurotransmitter release
by activating CB1 receptor-mediated inhibition of voltage-gated Ca
2+
channels [118, 156,
212]. Such a negative feedback mechanism should be effective in calming stimulated neurons
after excitation. Since then, dozens of papers have been published that have confirmed the
role of ECs as a retrograde messenger in various regions of the brain. It is now established
that EC release can be induced by four stimulation protocol, namely, postsynaptic
depolarization, activation of postsynaptic Gq-coupled receptors, combined Gq-coupled
activation and depolarization, and repetitive synaptic activation. In the following section, we
address the mechanisms of EC release by each of the four stimulation protocols.
(a) Depolarization-induced EC release
A number of recent studies have demonstrated that a well-known
form of short-term
plasticity at hippocampal GABAergic synapses,
called depolarization-induced suppression of
inhibition (DSI),
is in fact mediated by the retrograde actions of endocannabinoids
released in
response to depolarization of the postsynaptic
cells. Despite the widespread interest and
potential physiological importance of DSI, many questions regarding the
physiological
relevance of DSI remain. Brief activation of CA1 pyramidal cells in the hippocampus [2, 3,
159, 165-167] or Purkinje cells in the cerebellum [122, 204-206] (Fig. 4) is known to cause a
reduction in the amplitude of GABAergic inhibitory postsynaptic currents (IPSCs). The DSI
is initiated postsynaptically by the voltage-dependent influx of Ca
2+
into the soma and
dendrites of the neuron, but is expressed presynaptically through inhibition of transmitter
release from axon terminals of GABA interneurons. This suggests that a chemical messenger
generated during depolarization of the pyramidal neurons must travel backwards across the
synapse to induce DSI. DSI has been observed in both excitatory and inhibitory neurons in
hippocampal cell culture [158], in CA3 pyramidal cells [146], in dentate gyrus granule cells
[2], and in neocortical pyramidal cells [218].
The retrograde messenger in DSI remained unknown until recent investigations by
Wilson and Nicoll [211-213] and by Ohno-Shosaku et al. [156] indicated that in hippocampal
cells the messenger was likely to be an EC. Shortly thereafter, cerebellar DSI was also
reported to be mediated by an EC [62, 117, 216]. Furthermore, it was reported that CB1
receptor agonists selectively reduced IPSCs in both the hippocampus [83, 95, 108] and
cerebellum [194]. There is strong evidence that this retrograde signaling process involves an
EC. (a) CB1 receptor antagonists selectively blocked DSI whereas agonists enhanced it [156,
212]. (b) DSI is absent in CB1 receptor knockout mice [211, 216]. (c) The GABA
