One such model (Clopath et al., 2010, built on earlier work by Pfister and Gerstner, 2006) is based on interaction of presynaptic spikes with instantaneous and time-filtered postsynaptic membrane potential. At the synapse level, the model predicts the timing, rate and voltage-dependence of plasticity. On the network level, this learning rule stores information about both slow input correlations and rapid spatiotemporal sequences, depending on the structure of spike train input, thus capturing functional aspects of rate-dependent plasticity and STDP (Clopath et al., 2010). Hebbian STDP at glutamatergic synapses is mediated B-Raf inhibitor drug by

the same three signaling pathways that mediate most classical, correlation-dependent LTP and LTD. These are as follows: (1) NMDA receptor (NMDAR)-dependent LTP and (2) NMDAR-dependent LTD, in which correlated presynaptic release and postsynaptic depolarization trigger calcium influx through postsynaptic NMDARs (and voltage-sensitive calcium channels, VSCCs). LTP versus LTD induction is determined by the magnitude and time course of calcium flux, with brief, high calcium-generating LTP, sustained moderate calcium-generating LTD, and low calcium-inducing

no plasticity (Lisman, 1989; Yang et al., 1999). The primary expression mechanisms are postsynaptic, via addition or removal of postsynaptic AMPA receptors (AMPARs) and changes in single-channel conductance DAPT solubility dmso (Malinow and Malenka, 2002), though presynaptic expression can also occur. (3) Metabotropic glutamate receptor (mGluR)-dependent and/or cannabinoid type 1 receptor (CB1R)-dependent LTD, in which postsynaptic NMDARs are not involved, and LTD is expressed via a decrease in presynaptic transmitter release probability. This form is heterogeneous. In CB1R-dependent LTD, which is linked most strongly

to STDP, postsynaptic calcium and mGluR activation trigger dendritic synthesis of endocannabinoids, which diffuse retrogradely to activate CB1Rs on the presynaptic terminal and drive a long-lasting decrease Urease in release probability (Chevaleyre et al., 2006). Other forms of mGluR-LTD are CB1R-independent and postsynaptically expressed but are less linked to STDP. STDP is mediated by these three mechanisms, with postsynaptic spikes providing a critical component of postsynaptic depolarization for plasticity. There are two major, biochemically distinct forms of Hebbian STDP. One is composed of NMDAR-dependent LTP and NMDAR-dependent LTD (Figure 4A, left). This occurs at CA3-CA1 hippocampal synapses and some synapses on neocortical L2/3 pyramidal cells (Nishiyama et al., 2000; Froemke et al., 2005). Here, the magnitude of the NMDAR calcium signal determines the sign of plasticity (along with calcium from VSCCs) (Lisman, 1989).