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conclude that GluR1-dependent synaptic plasticity is the dominant form of LTP underlying
the acquisition of auditory and contextual fear conditioning, and that plasticity in distinct
amygdala pathways differentially contributes to aversive conditioning.
C. PKA, MAPK and CREB
The dependence of different forms of LA plasticity on cAMP/proteinkinase A (PKA) has
been widely investigated. For instance, LA-LTP can be inhibited by the PKA inhibitor Rp-8-
Cl-cAMPS (Schafe et al. 2000). Activation of PKA was also shown to accompany contextual
fear conditioning (Schafe et al. 1999). In coronal slices it has been demonstrated that besides
PKA mitogen-activated protein kinase (MAPK) is also critical for the expression of early
BLA-LTP (Merino and Maren 2006) as well as for the late phase of LTP in the LA (Huang et
al. 2000). In horizontal brain slices we have shown that the p38 mitogen-activated protein
(MAP) kinase inhibitor SKF 86002, provoke a reduction in LA-LTP (Schubert et al. 2007).
MAPK is also required for memory reconsolidation of auditory fear conditioning (Duvarci et
al. 2005).
It is known that the small GTPases of the Ras subfamily are activated by multiple
extracellular stimuli and, via a complex array of downstream effectors, control a variety of
cellular events that culminate in gene transcription. Mice that lack the neuronal-specific Ras
regulator, Ras-GRF (guanine-releasing factor), have severely impaired LTP in the amygdala
and display corresponding deficits in long-term memory for aversive events (Orban et al.
1999). Tetanus or forskolin-induced activation of MAPK can be blocked by
phosphatidylinositol 3-kinase (PI-3 kinase) inhibitors, which also inhibits cAMP response
element binding protein (CREB) phosphorylation (Lin et al. 2001). These results provide
novel evidence of a requirement of PI-3 kinase activation in the amygdala for synaptic
plasticity and memory consolidation, and this activation may occur at a point upstream of
MAPK activation.
As revealed by immunocytochemical studies, aversive training induced extracellular
signal-regulated kinase (ERK) phosphorylation and c-Fos expression specifically in the
ventral but not dorsal tip of LA (Radwanska et al. 2002). These data show for the first time
molecular differences
between subdivisions of LA as well as they also strengthen the idea that
neurons in the ventral tip of LA are involved in storage of long-lasting changes associated
with formation of fear memories.
The brain-specific striatal-enriched protein tyrosine
phosphatase (STEP) plays a key role in neuroplasticity and fear memory formation by its
ability to regulate ERK1/2 activation. STEP co-localizes with ERKs within LA neurons. A
substrate-trapping STEP protein binds to ERKs and prevents their nuclear translocation after
glutamate stimulation in primary cell cultures. Administration of TAT-STEP into the LA
disrupts LA-LTP and selectively disrupts fear memory consolidation (Paul et al. 2007).
CREB-mediated transcriptional regulation involves several signaling pathways, known to
mediate nuclear responses to diverse behavioral stimuli, along with coordinated interactions
with multiple other transcription activators, coactivators and repressors. Although fear
memory retrieval induces CREB phosphorylation and Fos expression within the amygdala
(Hall et al. 2001) and CREB-mediated transcription and protein synthesis are required for
instance for conditioned taste aversion memory (Josselyn et al. 2004; Lamprecht et al. 1997),
transgenic mice expressing a dominant-negative form of cAMP response element-binding
