Biology Reference
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2000). Furthermore, LTP at hippocampal inputs is associated with a sustained enhancement in
the release of dopamine in the PFC, measured by microdialysis (Gurden et al. 2000).
The mechanism of D1 receptor-mediated enhancement of LTP is likely to be via PKA
(Jay et al. 1998), which phosphorylates the AMPA receptor GluR1 subunit (Lee et al. 2000b)
and stimulates trafficking of GluR1 receptors into the postsynaptic density (Hu et al. 2007;
Man et al. 2007). Activation of PKA leads to activation of DARP-32 (Snyder et al. 1998) and
CREB, both of which have been found to be upregulated during late LTP at hippocampal-
mPFC synapses (Hotte et al. 2007), leading to gene transcription. Moreover, activation of
PKA by D1 receptors has also been shown to phosphorylate NMDA receptors, a process
which is involved in the D1-mediated activation of CREB (Dudman et al. 2003). Finally,
activation of D1 receptors can trigger insertion of AMPA receptors into the synaptic
membrane, when activated in conjunction with NMDA receptors (Sun et al. 2005). Thus,
activation of D1 receptors may increase the availability of extrasynaptic membrane-bound
AMPA receptors for synaptic insertion during LTP. This action in particular may contribute
to the “priming” effect of dopamine (Matsuda et al. 2006). In contrast, activation of D2
receptors reduces the surface expression of GluR1 AMPA receptors, suggesting a possible
mechanism for dopamine facilitation of LTD (Sun et al. 2005).
(ii) Cannabinoids
Activation of cannabinoid receptors, for example by inhalation of marijuana, is known to
produce cognitive and mnemonic deficits, together with alterations in sensory perception and
emotional processing (Ameri 1999; Sullivan 2000). Some of these effects may be mediated
by an action in the mPFC. For example, infusion of agonist ∆
9
THC (∆
9
tetrahydrocannabinol)
into the PFC has been shown to impair working memory tasks (Jentsch et al. 1997; Jentsch et
al. 1998), and cannabinoids have also been implicated in emotional learning (Marsicano et al.
2002; Chhatwal et al. 2005; Varvel et al. 2005; Laviolette and Grace 2006). Furthermore,
elevations in the endocannabioid system have been implicated in schizophrenia (Leweke et al.
1999; Ujike and Morita 2004). CB1 receptors, the cannabinoid receptor found in the brain,
are abundantly expressed in the mPFC (Herkenham et al. 1990; Marsicano and Lutz 1999;
Moldrich and Wenger 2000). As with other brain regions, CB1 receptors are localised on
excitatory terminals where they act presynaptically to reduce glutamate release (Auclair et al.
2000; Ferraro et al. 2001; Lafourcade et al. 2007). However their effectiveness at suppressing
inhibitory transmission is yet to be demonstrated in the mPFC.
CB1 receptors both mediate and facilitate LTD at inputs to layer 5 pyramidal neurons in
the mPFC. Following tetanic stimulation (4 trains of 100 stimuli at 100 Hz), activation of
CB1 receptors facilitates LTD induction over LTP induction at layer 5 to layer 5 synapses in
the rat prelimbic mPFC, while application of a CB1 receptor antagonist alone favours LTP
(Auclair et al. 2000). Moreover, a CB1 receptor-mediated LTD can be evoked at layer 2/3 and
layer 5/6 inputs to layer 5/6 neurons in the prelimbic mPFC of the mouse by tetanic
stimulation at moderate frequencies (10 Hz for 10 minutes; Lafourcade et al. 2007). LTD
evoked in this way is mediated by activation of postsynaptic mGluR5 receptors, leading to a
rise in intracellular calcium and activation of phospholipase C, and is expressed
presynaptically as a long-term reduction in transmitter release, mediated by the release of the
endogenous cannabinoid 2-acylglycerol (2-AG; Lafourcade et al. 2007). It is independent of
