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shown in brain slices derived either from eNOS
-/-
or nNOS
-/-
mice
(Kantor et al. 1996; O'Dell
et al. 1994).
Interestingly, we could demonstrate that increasing NO concentration by the NO-donor
SNAP caused LFS-induced LTD in wild-type mice, when EC fibers were stimulated
(Albrecht 2007), whereas LFS of EC fibers did not produce long-term reduction of synaptic
activity in drug-free slices as described above. In addition, Schafe and coworkers (2005)
showed that NO signalling is required for LTP at thalamic inputs to the LA and for the long-
term consolidation of auditory fear conditioning. Changes in NO production during fear
conditioning were also found by Sato and colleagues (2006). NO is known to affect synaptic
plasticity in various regions of the brain via the cGMP-cGMP-dependent protein kinase
(PKG) pathway. It has been found that the compound 3-(5-hydroxymethyl-2-furyl)-1-benzyl-
indazole (YC-1), a drug known to modulate the response of soluble guanylyl cyclase to NO,
greatly potentiated LTP in the amygdala (Chien et al. 2003). Therefore, the above mentioned
results suggest that LA-LTP and LA-LTD depends on NO-sensitive processes.
It is known from different studies that produced NO influences cyclooxygenase-2 (COX-
2) activity. We recently could recognized that there is a molecular cross-talk between COX-2
and NO that may regulate synaptic plasticity in the LA (Albrecht 2007). COX is a key
enzyme that converts arachidonic acid to prostaglandins. It has been revealed that selective
COX-2 inhibitors significantly reduced postsynaptic membrane excitability, back-propagating
dendritic action potential-associated Ca
2+
influx, and LTP induction in hippocampal dentate
granule neurons and CA1 neurons, while COX-1 inhibitors were ineffective (Chen et al.
2002; Murray and O'Connor 2003; Slanina et al. 2005). In addition, recent behavioral data
indicate that COX-2 is a required biochemical component mediating the consolidation of
hippocampus-dependent memory (Teather et al. 2002).
The functional significance of COX-2 in the amygdala is unclear, although it is expressed
at high levels (Kaufmann et al. 1996). A comparably high packing density of COX-2 positive
neurons has been also observed in the LA (Bidmon et al. 2000). Our recent data provide the
first evidence that COX-2 contributes to plasticity changes in the amygdala. We demonstrated
that the selective COX-2 inhibitor NS-398 significantly reduced
the probability of LA-LTP
induction. The involvement of COX-2 in mediating of LA-LTP is supported by the decrease
in LA-LTP in animals lacking the inducible enzyme COX-2 (Albrecht 2007). The reduced
paired pulse facilitation obtained in our experiments in heterozygous COX-2 deficient mice
and in NS-398-treated mice suggests an involvement of presynaptic mechanisms. COX-2
might act as a retrograde signal that participates in presynaptic aspects of plasticity in the LA.
In this way the impairment of LTP in homozygous COX-2 deficient mice could be explained
by a reduced glutamate release.
In addition, recent data provide solid evidence for retrograde endocannabinoid signalling
at least in the BLA and also indicate that this retrograde signalling requires only a
postsynaptic neuron and attached synaptic boutons (Zhu and Lovinger 2005).
Endocannabinoids are fatty acid derivatives that have a variety of biological actions, most
notably via activation of the cannabinoid receptors. These receptors are also targets for drugs
derived from
Cannabis sativa
.
In the nervous system, endocannabinoids act as
neuromodulators that depress neurotransmitter release at
presynaptic terminals
.
In the
amygdala, endocannabinoid signalling has been implicated in learning and memory,
specifically in extinction of aversive memories (Marsicano et al. 2002). It has been also
