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(Milad and Quirk 2002; Barrett et al. 2003; Burgos-Robles et al. 2007). Since increases in
activity in the prelimbic mPFC have been observed during expression of conditioned fear
responses (Baeg et al. 2001; Gilmartin and McEchron 2005; Laviolette et al. 2005; Vidal-
Gonzalez et al. 2006), this suggests that the correlations between synaptic plasticity and
retrieval of the extinction versus fear memory may be confounded by other factors. For
example the field recordings used in these experiments are average responses of many
neurons. It is possible that there are distinct populations of pyramidal neurons within the
prelimbic mPFC that encode fear versus extinction memories.
Since most inputs from the mPFC to the amygdala are excitatory (Smith et al. 2000;
Likhtik et al. 2005) and neurons in the basolateral amygdala still fire during extinction,
despite the animal showing less fear (Repa et al. 2001), this suggests that enhanced activity of
the mPFC has effects on the amygdala that are downstream of the basolateral amygdala. This
may be via direct activation of intercalated neurons in the amygdala (McDonald et al. 1996),
which could act to inhibit fear memory expression in the amygdala (Maren and Quirk 2004;
Pare et al. 2004). Intercalated neurons are GABAergic neurons that act as an inhibitory gate
between the basolateral amygdala, which receives inputs containing information regarding the
conditioned stimulus, and the central amygdala, the output station of the amygdala that
projects to the brainstem to initiate the fear response (Royer et al. 1999; Sah et al. 2003).
Stimulation of the infralimbic mPFC evokes c-fos expression in intercalated neurons (Berretta
et al. 2005), and inhibits the responsiveness of central amygdala neurons to stimulation of the
basolateral amygdala (Quirk et al. 2003). Furthermore, intercalated neurons show both LTP
and LTD (Royer and Pare 2002), suggesting that plasticity at mPFC inputs to intercalated
neurons may underlie extinction.
Connections between the mPFC and hippocampus have also been implicated in fear
conditioning and extinction. For example, fear memories overcome extinction memories
when presented in a new context. Furthermore hippocampal inputs and outputs both show
prolonged synaptic plasticity associated with traumatic memories, which outlasts extinction
of the memory, and hippocampal synaptic efficacy is altered during re-exposure to the
conditioned stimulus (Garcia and Jaffard 1996; Garcia et al. 1998). When development of
LTP at hippocampal-mPFC synapses following extinction training is prevented by low
frequency stimulation of the ventral hippocampus, recall of the extinction memory is
impaired (Farinelli et al. 2006). Furthermore long-term changes are seen in the hippocampus
during consolidation of extinction in the inhibitory avoidance paradigm. These are dependent
on NMDA receptors, MAP kinase, PKA, gene expression and protein synthesis (for review
see Quirk and Mueller 2008), suggesting that synaptic plasticity in the hippocampus, or at
hippocampal inputs to the mPFC, also contributes to the consolidation of extinction.
In summary, the mPFC is involved in both the expression of fear memories, and the
expression and retrieval of extinction (Vidal-Gonzalez et al. 2006). Changes that occur in the
mPFC during extinction expression and retrieval involve regulation by many molecular
markers and receptors that are involved in synaptic plasticity, implicating synaptic plasticity
in the mPFC and at connections between the mPFC, the amygdala and the hippocampus as
the cellular basis of extinction memories. While synaptic plasticity can be induced in the
prelimbic mPFC following stimulation of the basolateral amygdala (Maroun and Richter-
Levin 2003), few studies to date have investigated the mechanisms underlying synaptic
plasticity in the infralimbic mPFC and at connections between the infralimbic mPFC and the
amygdala (Maroun 2006), which may be more relevant to extinction. Understanding these
