Biology Reference
In-Depth Information
High frequency (two brief 100Hz trains) stimulation of Schaffer collaterals releases
glutamate, which activates postsynaptic mGluR1/5, leading to the production of 2-AG
through the PLCĪ²-DAGL pathway. 2- AG is then released, activates presynaptic CB1 on
nearby GABAergic interneurons, and causes long-term suppression of GABA release, if CB1
activation continues for several minutes [42]. Further, the expression of LTDi facilitated
subsequent induction of LTP at excitatory synapses [42, 217]. Enhancement of LTP likely
results from mechanisms
similar to those previously implicated in priming of LTP during
EC-
mediated DSI and LTDi [35, 43]. Facilitation of LTP induction
by mGluR activation was also
observed in a previous study [145], and similar EC actions may underlie
this enhancement. It
is likely that mGluR5 and CB1 blockade
prevent stimulus-primed LTP by interfering with EC
signaling during low frequency stimulation. However, application of SR141716 after low
frequency stimulation (LFS) but
during theta
burst stimulation (TBS) does not abolish the
LFS facilitation of LTP. Thus,
CB1 activation is not directly involved in LTP induction.
Because EC signaling is blocked when the CB1 antagonist
is present during TBS, no DSI
would take place during LTP induction,
and thus LFS-enhanced DSI could not contribute to
LTP enhancement [42, 217]. Up-regulation of retrograde EC signaling and LTDi
contribute to
long-lasting enhancement of glutamatergic transmission
through inhibition of GABAergic
transmission [217]. These processes
might thus contribute to EC enhancement of learning
and
memory.
Therefore, the EC signaling could significantly contribute to the memory formation
through the induction of local metaplasticity. LTP elicited by moderate stimulations (20 or 50
pulses) was facilitated in slices treated with a CB1 antagonist, whereas LTP elicited with
robust stimulations (100 or 200 pulses) was unchanged by CB1 blockade. LTP elicited with
TBS also was facilitated with CB1 blockade, revealing a tonic inhibitory influence of ECs on
the hippocampal LTP induction. Conversely, inhibition of cyclooxygenase-2 (COX-2)
prevented LTP elicited with TBS. Inhibition of COX-1 or other routes of EC degradation did
not affect LTP. These observations suggest that COX-2 regulates the formation of ECs that
negatively regulate LTP [180]. Possible involvement of the EC system in extinction processes
has been suggested in a behavioral study [201]. Performance of CB1-knockout mice was
evaluated in the Morris water maze test, a standard task for examination of hippocampus-
dependent spatial memory in rodents. CB1-knockout mice exhibited a deficit in learning a
new platform location during the reversal text suggesting that the EC signaling plays a key
role in facilitating extinction processes [201]. In contrast, CB1-knockout mice exhibited
normal acquisition and extinction of trace eyeblink conditioning that is known to be
dependent on the hippocampus [113]. Animals treated with a low dose of SR
intrahippocampally enhanced learning and memory without effecting the procedural learning
[171]. It remains to be investigated the extent to which EC-LTDi contributes to extinction
processes of hippocampus-dependent learning. All these observations support the notion that
spatial learning may activate ECs and stimulate CB1 receptors in hippocampus. Although the
molecular identity of the retrograde signal involved in DSI/DSE is not fully determined, two
studies have suggested that 2-AG mediates DSI. DSI in CA1 pyramidal cells was not affected
by FAAH inhibition but was prolonged by inhibition of COX-2, which can degrade both 2-
AG and AEA [110]. Because FAAH inhibition was shown to facilitate the effect of
exogenously applied AEA, the negative effect of FAAH inhibition on DSI suggests that AEA
does not play a dominant role in DSI. The inhibitors of MAGL (URB754 and URB602)
increased 2- AG levels and prolonged DSI in CA1 pyramidal cells, suggesting the
involvement of 2-AG [130]. However, third study suggests that DSI was not affected by
