These properties can allow asynchronously activated distal synapses to overcome their relative CP-690550 supplier electrotonic disadvantage compared with proximal synapses and exert a paradoxically greater influence on action potential output. Furthermore, the differential sensitivity to input timing makes proximal inputs more suited for temporal coding, and distal inputs, for rate coding. The fact that these differences exist along individual dendrites indicates that single dendrites are not uniform compartments, and that the computational strategy

of individual synaptic inputs may depend on their precise location along the dendrite. Using a combination of experimental and modeling approaches, we demonstrate that the synaptic integration gradients result from a combination of two basic biophysical features of single dendrites. First, dendritic nonlinearities, including NMDAR conductances, VGCCs, and VGSCs, must be recruited by increasing numbers of synaptic inputs.

Previous studies have demonstrated that synchronous clustered input can recruit such dendritic nonlinearities in neocortical pyramidal cells (Major et al., 2008, Nevian et al., 2007, Selisistat Polsky et al., 2004 and Schiller et al., 2000), which can help to enhance synaptic gain (Larkum et al., 2004) and compensate for the electrotonic filtering of distal inputs (Cook and Johnston, 1997 and Cook and Johnston, 1999). The second, crucial, ingredient is the gradient of input impedance that exists along single dendrites, a consequence of the impedance load as the dendritic branch meets its parent trunk (or the soma) and the end effect at the tip of the dendrite (Jack et al., 1975 and Rinzel and Rall, 1974). These two factors work in concert to generate the observed gradient in integrative properties along each dendrite. Given that these two properties—dendritic nonlinearities and impedance gradients—are found in most neurons, this suggests that the observed

Cediranib (AZD2171) synaptic integration gradients may be a general feature of neurons in the central nervous system. It is important to note that the synaptic integration gradients we have observed do not require any underlying gradients in the properties of the synapses or in the dendritic distribution of voltage-gated channels. Indeed, in our model we could reproduce our experimentally observed integration gradients using entirely uniform synaptic parameters and densities of voltage-gated channels; thus, the gradients arise solely from the nonuniform electronic architecture intrinsic to the fundamental asymmetry of dendritic structure. In neurons exhibiting dendritic gradients of synaptic properties (Katz et al., 2009 and Magee and Cook, 2000) or voltage-gated channels (Lörincz et al., 2002, Magee, 1999, Mathews et al., 2010 and Williams and Stuart, 2000), these will be superimposed on, and may modify, the synaptic integration gradients that we have demonstrated.