Biology Reference
In-Depth Information
time. LTP, the long lasting enhancement of synaptic transmission first reported by Bliss and
Lomo [26] over 30 years ago, has been the focus of an enormous amount of investigation.
The temporal pattern of synaptic stimulation determines whether synaptic efficacy is
strengthened (long-term potentiation, LTP) or weakened (long-term depression, LTD). LTP
represents long-lasting 'memory' at the sub-neuronal level and is widely believed to underlie
learning and memory at the behavioral level. Since it's discovery in the perforant path of the
hippocampal formation, the great majority of the work related to LTP has been through
electrophysiological investigations. During this time, evidence for a number mechanisms for
the induction and expression of this functionality have been reported including increased
glutamate release (pre-synaptic mechanism,) and activation of previously silent synapses
[102]. Long-term memory involves altered gene expression, protein synthesis and the growth
of new and stronger synaptic connections within existing circuits. Intracellular signaling
pathways convert short-lasting stimulus events to persistent changes in synaptic strength.
(A) Regulation of long-term synaptic plasticity by ECs
As in EC-mediated short-term plasticity, all the studies to date suggest that EC-mediated
long-term plasticity takes the form of depression of neurotransmission in various brain
regions. It was observed that long-term depression (LTD) was absent in CB1 receptor
knockout mice, reduced or eliminated by CB1 receptor blockade, and enhanced by CB1
receptor activation in various brain regions, indicating the involvement of EC signaling [74].
Soon after this publication, similar EC mediated LTD was reported at both excitatory (LTDe)
and inhibitory (LTDi) neurotransmission in various brain regions [42, 136, 170]. Another
form of EC-mediated LTDe was described in the visual cortex [179]. All these forms of EC-
mediated LTD expressed presynaptically as persistent decrease in neurotransmitter release.
By contrast, cerebellar LTD, which is well known to be expressed postsynaptically, was
reported to require EC signaling [174]. In the following sections, we describe these different
LTD's and also discuss the functional significance of the EC signaling in various neuronal
functions.
(B) Evidence for EC retrograde messengers in long-term synaptic plasticity
(a) Dorsal Striatum
In 1997, it was demonstrated that high frequency stimulation (for example, 100 Hz, 1 s)
of corticostriatal glutamatergic afferents in medium spiny neurons of the dorsal striatum was
known to induce LTD of the excitatory input. This striatal LTDe was suggested to be
expressed as long-lasting suppression of glutamate release through the elevation of
postsynaptic Ca
2+
, implying the involvement of a retrograde signal [34, 45, 46]. It should be
noted here the critical role of postsynaptic intracellular Ca
2+
in the formation of ECs, because
there are strong evidences that AEA synthesis is stimulated by Ca
2+
signaling [61, 68].
Moreover, striatal medium spiny neurons grown in culture had been shown to synthesize and
release AEA, in a Ca
2+
-dependent manner, in response to depolarizing stimuli[61].
Furthermore, striatal LTD is dependent on activation of D2 (as well as D1) dopamine
receptors. Accordingly, depolarization and D2 receptor activation led to an increased
detection of AEA measured in the dorsal striatum of rats in vivo, and that these effects were
additive [76]. Based on these discoveries, it was expected that ECs might work as retrograde
