Biology Reference
In-Depth Information
shown that amphetamine-induced LA-LTD can be blocked by the cannabinoid CB1 receptor
antagonist AM251 (Huang et al. 2003).
IV.
S
IGNALING
E
VENTS
T
HAT
F
OLLOW
LA-LTP
I
NDUCTION
LTP is a complex mechanism consisting of distinct phases that involve different
molecular mechanisms. The early phase (E-LTP) is independent on protein synthesis, while
the more persistent long-lasting LTP (L-LTP), which lasts several hours in vitro and days and
weeks in vivo, requires synthesis of new proteins. Some authors also distinguish an
intermediate phase (Matthies et al. 1990).
Much of the work on NMDAR-dependent LTP or LTD in the LA has focused on the
mechanisms responsible for the initial increase in synaptic strength lasting 30-60 min. Of
greater interest and importance are, however, the mechanisms that allow LTP or LTD to
persist hours, days, or even weeks. It is now well established that late LA-LTP requires gene
transcription and the synthesis of new proteins. In contrast to L-LTP studies, studies of late
LA-LTD in the LA are currently largely unknown.
A. Ca
2+
/calmodulin-dependent protein kinase II
After the discovery that increased calcium concentration in the postsynaptic cell, as a
consequence of NMDA receptor activation, is a critical factor in the induction of LA-LTP, the
analysis of the downstream cellular consequences of this calcium influx has gained
considerable interest. Ca
2+
/calmodulin-dependent protein kinase II (CaMKII) is known to
play a critical role in synaptic plasticity and memory formation in a variety of learning
systems and species. Consistent with the evidence that fear conditioning results in an increase
of the autophosphorylated (active) form of CaMKII-alpha in LA dendritic spines (Rodrigues
et al. 2004), the bilateral post-training intracerebral infusion of KN62, a specific inhibitor of
CAMKII, causes retrograde amnesia in rats (Wolfman et al. 1994). The intra-amygdala
infusion of KN-62, dose-dependently impaired the acquisition, but not the expression, of
auditory and contextual fear conditioning. In accordance with these behavioral data the
NMDA-dependent form of LTP at thalamic input synapses to the LA was impaired by KN-62
administration (Rodrigues et al. 2004). CaMKII-alpha is postsynaptic to auditory thalamic
inputs and co-localizes with the NR2B subunit of the NMDA receptor (Rodrigues et al.
2004). It is known that the NR2B subunit of the NMDA receptor is tyrosine-phosphorylated
in the brain, with Tyr-1472 being the major phosphorylation site. Mice with a knock-in
mutation of the Tyr-1472 site to phenylalanine (Y1472F) show impaired fear-related learning,
reduced LA-LTP, and impaired NMDAR-mediated CaMKII signaling (Nakazawa et al.
2006). In addition, in NMDA receptor-deficient mice it has been shown that CaMKII-beta
and CaMKII-alpha activation involves the NR2A subunit in the lateral/basolateral amygdala
during memory retrieval following auditory fear conditioning. These results suggest that
auditory fear conditioning also involves a linkage between NR2A of NMDAR and the
CaMKII cascade (Moriya et al. 2000). Moreover, an up-regulation in the expression of the
endogenous inhibitor gene CaMKIIN-alpha during consolidation of fear memory has been
