, 2010). In other cases, bAPs prime the dendrite to produce synaptically evoked calcium spikes which mediate STDP-LTP (Zhou et al., 2005; Kampa et al., 2006) For more on dendritic excitability and STDP, see Sjöström et al. (2008). The decremental propagation of bAPs creates a profound spatial gradient of STDP in neurons. In L5 pyramidal cells in neocortex, brief pre- and postsynaptic spike trains evoke Hebbian STDP at proximal synapses (<100 μm from soma) but progressively less LTP at more distal synapses. The most distal synapses (>500 μm) show only anti-Hebbian LTD in

response to pre-leading-post pairing. Distal LTD can be converted to LTP by supplying sufficient dendritic depolarization to either enhance bAP propagation (Sjöström and Häusser, 2006) or convert the single bAP into a dendritic-somatic spike burst (Letzkus et al., 2006). Smaller L2/3 Entinostat in vitro pyramidal cells exhibit a similar Endocrinology antagonist trend in which distal synapses express less STDP and a broader LTD window than proximal synapses (Froemke et al., 2005). Thus, decremental bAP propagation creates distinct dendritic plasticity zones in which different rules for synapse modification exist ( Figure 4B; Kampa et al., 2007; Spruston, 2008). In general, the most proximal synapses experience the strongest bAPs and are expected to exhibit Hebbian STDP with minimal requirements for synaptic cooperativity

and firing rate. More distal synapses will exhibit LTD-biased Hebbian STDP ( Froemke et al., 2005) or anti-Hebbian LTD ( Sjöström and Häusser, 2006) and will require high firing rates or strong synaptic convergence for Hebbian STDP. These synapses can exhibit anti-Hebbian STDP, if post-leading-pre firing drives synaptically evoked calcium spikes ( Kampa et al., 2006; Letzkus et al.,

Fenbendazole 2006). Very distal synapses may be largely outside the influence of bAPs, so that STDP is absent and plasticity is induced by cooperative firing of neighboring inputs that evokes dendritic sodium or calcium spikes or regenerative NMDA spikes ( Golding et al., 2002; Gordon et al., 2006). The existence of different plasticity rules within dendritic regions may contribute to activity-dependent stabilization of different functional classes of synapses in these regions ( Froemke et al., 2005). Modulation of dendritic excitability will regulate both the shape of STDP rules and the spatial extent of dendritic plasticity zones, including increasing or decreasing the prevalence of STDP relative to local, associative forms of plasticity. Neuromodulation has robust effects on the spike timing dependence of plasticity. This includes gating of STDP, as in adult visual cortex slices, where exogenous activation of receptors coupled to adenylate cyclase (e.g., β-adrenergic receptors) and PLC (e.g., muscarinic acetylcholine receptors) are necessary for LTP and LTD, respectively, within Hebbian STDP (Seol et al., 2007).