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et al. 2006), suggesting that calcium influx through NMDA receptors is required for this form
of LTP.
(c) Spike timing-dependent plasticity
Spike timing-dependent plasticity (STDP) is a paradigm that pairs presynaptically evoked
EPSPs with postsynaptic action potentials (Dan and Poo 2004; Letzkus et al. 2007). This is
highly likely to occur physiologically since both the pre- and postsynaptic neurons are
invariably simultaneously active in vivo (Letzkus et al. 2007). During this Hebbian form of
plasticity, pairing needs to occur within a specific temporal window, and the direction of
plasticity depends on the timing of the presynaptic activity in relation to the postsynaptic
activity, generating a “tuning” curve. In general, pairing trains of action potentials before
trains of EPSPs leads to LTD, whereas pairing action potentials after EPSPs leads to LTP
(Dan and Poo 2004; Letzkus et al. 2007).
A few studies have examined STDP in the mPFC. Pairing action potentials 5 ms after the
start of a train of EPSPs (50 times repeated at 0.1 Hz) evokes LTP at layer 2/3 inputs to layer
5 pyramidal neurons in mice (Couey et al. 2007; Meredith et al. 2007). However a delay of 10
ms between the EPSP onset and the action potentials fails to evoke LTP, both in mice
(Meredith et al. 2007) and rats (evoked by EPSP-spike pairings of 10 bursts of 5 stimuli at 20
Hz; Huang et al. 2007a). In mice, when the action potential precedes the EPSP by 0-10 ms or
40-70 ms, LTD is evoked, with no plasticity evoked at intermediate delays (Meredith et al.
2007). It remains to be seen if a similar temporal profile of STDP is seen in layer 5 pyramidal
neurons in the rat. LTP evoked by STDP requires a rise in intracellular calcium, and can be
blocked by application of nicotine (10 µM), via activation of GABAergic interneurons. This
subsequently decreases the dendritic calcium rise (Couey et al. 2007), which is essential for
eliciting STDP (Magee and Johnston 1997; Koester and Sakmann 1998).
In summary, while the majority of synapses in the mPFC are plastic, there appears to be a
delicate balance between LTP and LTD, with one often masking the other (Hirsch and Crepel
1991; Law-Tho et al. 1995; Otani et al. 1998; Auclair et al. 2000; Matsuda et al. 2006). Thus
the same induction protocol can evoke either LTP or LTD. This contrasts with other brain
regions where high frequency stimulation (50-100 Hz) typically evokes LTP, while low
frequency stimulation (1 Hz) typically evokes LTD. The reason for this is not clear, but
calcium imaging studies would help to elucidate what underlies these mechanistic
discrepancies.
Synaptic plasticity is differentially regulated by dopamine, depending on the induction
mechanism and prior exposure. These findings may be confounded by the release of
endogenous dopamine in the slice during the stimulation protocol (Calabresi et al. 1995;
Young and Yang 2005), with the amount of residual dopamine in the brain slice depending on
the timing of recording following the brain dissection (Otani et al. 2003; Young and Yang
2005), and with bursts more likely to evoke higher concentrations of transmitter release from
dopaminergic afferent fibres (Goto et al. 2007). Therefore in future studies it would be useful
to investigate the action of selective dopamine receptor antagonists alone on these forms of
synaptic plasticity, to investigate plasticity at a range of times following dissection, and to
investigate the effects of a range of concentrations of dopamine (i.e. 3 µM versus 100 µM;
Seamans and Yang 2004). Indeed, Matsuda and colleagues found that 3 µM dopamine did not
trigger LTD when combined with tetanic stimulation (Matsuda et al. 2006).
