Biology Reference
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way require a rise in postsynaptic calcium (Hirsch and Crepel 1992). However there is
controversy as to the role of NMDA receptors in synaptic plasticity in the mPFC. While early
studies showed that LTP is converted to LTD in the presence of AP5 (Hirsch and Crepel
1991; Law-Tho et al. 1995), later studies found that AP5 blocked both LTP and LTD at layer
2/3 inputs (Vickery et al. 1997; Otani et al. 2002; see below).
(a) LTD induction
LTD can be induced in several ways at layer 5 synapses following stimulation of the
superficial layers. Firstly, LTD can be induced by tetanic stimulation (4 trains of 100 stimuli
at 50 Hz) in the presence of a high concentration of dopamine (100 µM; Otani et al. 1998).
Secondly, LTD can be evoked by tetanic stimulation in the presence of a group 1
metabotropic glutamate receptors (mGluR) agonist (Otani et al. 1999). Thirdly, two types of
chemical LTD that do not require tetanic stimulation can be evoked. One can be induced by
application of a group 2 mGluR agonist alone (Otani et al. 2002; Barbara et al. 2003), while
the other can be evoked by dopamine in the presence of an mGluR1 agonist (Otani et al.
2002; Barbara et al. 2003). Finally, LTD can be evoked by low frequency stimulation (3 Hz
stimulation for 15 minutes), in the presence of a very high concentration of dopamine (200
µM; Huang et al. 2004).
LTD evoked by tetanic stimulation in the presence of dopamine is blocked by antagonists
at both D1 and dopamine type-2 (D2) receptors, antagonists of either group 1 and group 2
mGluRs, and by chelating postsynaptic calcium (Otani et al. 1998; Otani et al. 1999).
However this type of LTD is not NMDA receptor-mediated. In contrast, mGluR2-evoked
LTD (in the absence of tetanic stimulation) can be blocked by AP5 (Otani et al. 2002). This
form of LTD is induced postsynaptically through activation of phospholipase C, which
releases calcium from inositol triphosphate (IP
3
)-sensitive intracellular stores, and activates
phospholipase D, protein kinase C (PKC) and protein kinase A (PKA; Otani et al. 2002).
However it is expressed presynaptically, as shown by a sustained increase in the paired pulse
ratio, and can be occluded by a cannabinoid CB1 receptor agonist, suggesting that
cannabinoids mediate the presynaptic expression (see below; Barbara et al. 2003). The link
between NMDA receptor activation and group 2 mGluRs has not been ascertained, but is
likely to be due to a critical concentration of calcium being reached at the synapse.
The common mechanism for tetanic stimulation-evoked and group 1 mGluR-induced
LTD is via convergent activation of mitogen-activated protein kinases (MAP kinases). These
forms of LTD are blocked by a MAP kinase inhibitor, and phosphorylation of MAP kinases is
observed in the presence of dopamine and group 1 mGluR agonists (Otani et al. 1999). The
function of MAP kinases in the PFC is currently unknown, but in the hippocampus MAP
kinases are necessary for phosphorylation of cyclic AMP response element-binding protein
(CREB) by PKA and PKC (Roberson et al. 1999), for triggering transcription, and for
modifying spine shape (Wu et al. 2001).
Finally, LTD evoked by low frequency stimulation is blocked by both D1 and D2
receptor antagonists, a PKA inhibitor and by the mGluR antagonist methyl-4-
carboxyphenylglycine (MCPG), but not by AP5 (Huang et al. 2004), similar to LTD evoked
by dopamine coupled with tetanic stimulation at 50 Hz (Otani et al. 1998). The generation of
LTD in the presence of dopamine with this stimulation protocol is blocked in the D1 receptor
heterozygote knockout mice, which express 50% of the wildtype levels of D1 receptors,
showing the action of dopamine is mediated by D1 receptors.
