Biology Reference
In-Depth Information
When PF stimulation was combined with CF stimulation (100 Hz, 5 pulses), only two to five
pulses to PFs were enough to induce EC release [29]. This associative short-term plasticity
induced by coactivation of PF and CF synapses was also dependent on both mGluR1
activation and postsynaptic Ca
2+
elevation. In VTA dopamine neurons, brief-burst stimulation
(5 Hz, 10 pulses) of excitatory inputs from the prefrontal cortex induced EC-mediated
suppression of the excitatory transmission, which was sensitive to both mGluR1 antagonist
and the blockade of postsynaptic Ca
2+
elevation [144]. All these observations indicate the
significance of Ca
2+
-assisted receptor-mediated pathway for synaptically triggered EC
release. In addition, the other two pathways, namely, the depolarization induced pathway
being mediated by Ca
2+
elevation alone [29] and the receptor-driven pathway being triggered
by Gq-coupled receptor activation alone [127], can also be involved in the synaptically
triggered EC release. Besides the temporal pattern, the spatial pattern of synaptic activation is
also important for EC signaling in the cerebellum. Although spatially dispersed synapse
activation failed to induce retrograde EC signaling, activation of nearby synapses induced
retrograde inhibition of PF-PC synapses, because of activation of mGluRs by glutamate
spillover from nearby active synapses [135].
(B) CB1-Dependent Suppression of Transmitter Release: Presynaptic Mechanisms
EC release during short-term plasticity activates presynaptic CB1 receptors and
suppresses transmitter release reversibly. Several studies addressed the issue of how
activation of CB1 receptors affect transmitter release [2]. Three mechanisms have been
suggested for the CB1-mediated suppression of transmitter release, which include inhibition
of voltage-gated Ca
2+
channels, activation of K
+
channels, and inhibition of release
machinery. First, the possibility of Ca
2+
channel inhibition has been most intensively studied
and well supported by many lines of evidence. CB1 receptors are pertussis-sensitive G-
protein-coupled receptors, and their activation inhibits L-type, N-type, and Q-type Ca
2+
channels [39, 40, 125, 162, 195]. The studies using Ca
2+
-channel blockers and K
+
-channel
blockers suggested that the cannabinoid-mediated suppression was caused by inhibition of
presynaptic Ca
2+
channels rather than activation of K
+
channels in the hippocampus and
cerebellum [31, 95]. Second, the possibility of K
+
-channel activation has also been suggested
[51, 52, 63]. It is thought that activation of K
+
channels changes the action potential wave
form and indirectly suppresses the Ca
2+
influx into presynaptic terminals. Third, inhibition of
the release machinery has also been suggested to contribute to CB1-mediated suppression of
transmitter release [194, 215]. In some cells, it appears that the CB1 receptor could reduce
GABA release from at least some nerve terminals through a mechanism that is independent of
N-P/Q-type Ca
2+
channels [73, 194, 200, 202], perhaps by direct action on the transmitter
release machinery. In cerebellar PCs, CB1 activation had no effect on basal miniature
postsynaptic events but selectively suppressed miniature postsynaptic events enhanced by
Ca
2+
elevation in presynaptic terminals [215]. Thus, CB1 activation appears to regulate
processes of spontaneous transmitter release by acting downstream of Ca
2+
entry into
presynaptic terminals.
2.3.2 Long-term synaptic plasticity
In addition to short-term plasticity, central synapses often show long-term plasticity that
is they are capable of increasing or decreasing their efficacy of transmission in response to
brief repetitive synaptic activation and thereafter maintaining the changed efficacy for a long
