Different forms of STDP are often intermixed in a seemingly synapse-specific manner. For example, parallel fiber synapses onto fusiform cells in the dorsal cochlear nucleus exhibit Hebbian STDP, while those onto cartwheel neurons show anti-Hebbian LTD (Tzounopoulos et al., 2004). STDP rules also vary by postsynaptic cell type in Selleck Nintedanib striatum (Fino et al., 2008; 2009). However, STDP is also dramatically shaped by dendritic depolarization and neuromodulation. For example, anti-Hebbian

LTD on cortical pyramidal cells is converted into Hebbian STDP by manipulations that depolarize dendrites or promote the spread of back-propagating action potentials (bAPs) (Sjöström and Häusser, 2006; Letzkus et al., 2006; Zilberter et al., 2009), and Trametinib solubility dmso dopamine and inhibition alter the sign of STDP in the hippocampus and striatum (Fino et al., 2005; Shen et al., 2008; Zhang et al., 2009). The combination of synapse specificity and modulation may be useful in specializing different synapses for different types

of information storage, while providing dynamic control over plasticity. STDP depends not only on spike timing, but also on firing rate, synaptic cooperativity, and postsynaptic voltage (Markram et al., 1997; Sjöström et al., 2001). Cooperativity refers to the need for multiple coactive synaptic inputs to generate sufficient depolarization (or spiking) to drive LTP in classical hippocampal experiments (McNaughton et al., 1978). In slice experiments, unitary connections (which lack cooperativity and generate only modest dendritic depolarization) exhibit Hebbian STDP only when pre- and postsynaptic spikes occur at moderate firing rates (10–20 Hz). Higher firing rates (>30 Hz) induce LTP independent of spike timing, and lower firing rates (<10 Hz) generate only LTD for pre-leading-post spike intervals (Markram et al., 1997; Sjöström et al., 2001; Wittenberg and Wang, 2006; Zilberter et al., 2009).

Thus, Hebbian STDP operates primarily in a permissive middle range of firing frequency, superimposed on a standard Bienenstock, Cooper & Munro (BCM) plasticity function in which high firing rates drive LTP, and low firing rates drive LTD (Bienenstock et al., 1982; Figures 3A and 3B). The underlying constraint is all that LTP requires additional postsynaptic depolarization beyond a pre- and postsynaptic spike. This depolarization can also be provided by cooperative activation of multiple nearby synapses, which allows Hebbian STDP to be induced at lower frequency (Sjöström et al., 2001; Stuart and Häusser, 2001; Sjöström and Häusser, 2006; Figure 3C). The firing rate and depolarization requirements demonstrate that a single postsynaptic somatic spike is not a sufficient signal for associative plasticity, nor the basis for cooperativity—multiple spikes are required, and these must interact with local dendritic depolarization produced in part by spatial summation of local synaptic potentials.