Synaptic Integration Gradients in Single Cortical Pyramidal Cell Dendrites

Abstract

Cortical pyramidal neurons receive thousands of synaptic inputs arriving at different dendritic locations with varying degrees of temporal synchrony. It is not known if different locations along single cortical dendrites integrate excitatory inputs in different ways. Here we have used two-photon glutamate uncaging and compartmental modeling to reveal a gradient of nonlinear synaptic integration in basal and apical oblique dendrites of cortical pyramidal neurons. Excitatory inputs to the proximal dendrite sum linearly and require precise temporal coincidence for effective summation, whereas distal inputs are amplified with high gain and integrated over broader time windows. This allows distal inputs to overcome their electrotonic disadvantage, and become surprisingly more effective than proximal inputs at influencing action potential output. Thus, single dendritic branches can already exhibit nonuniform synaptic integration, with the computational strategy shifting from temporal coding to rate coding along the dendrite.

Cell-intrinsic drivers of dendrite morphogenesis

“…The development of new approaches for studying dendrite morphogenesis (see Box 2) has led to the view that axons and dendrites work in concert to define neuronal connectivity. A key concept that has emerged from such functional studies is that the particular shapes of dendrites are intimately tied to the proper wiring of neuronal circuits and their function (Häusser et al, 2000;Parrish et al, 2007b;Branco et al, 2010;Branco and Häusser, 2011;Gidon and Segev, 2012; Lavzin et al, 2012).…”

“…The development of new approaches for studying dendrite morphogenesis (see Box 2) has led to the view that axons and dendrites work in concert to define neuronal connectivity. A key concept that has emerged from such functional studies is that the particular shapes of dendrites are intimately tied to the proper wiring of neuronal circuits and their function (Häusser et al, 2000;Parrish et al, 2007b;Branco et al, 2010;Branco and Häusser, 2011;Gidon and Segev, 2012; Lavzin et al, 2012).Prior to the elaboration of dendrites, neurons undergo axodendritic polarization, whereby the morphologically and functionally distinct axonal and dendritic compartments (see Box 3) are specified. In most neurons, including retinal ganglion neurons, forebrain pyramidal neurons and cerebellar granule neurons, the generation of an axon precedes the development and elaboration of dendrites (Ramón y Cajal, 1995).…”

Modeling Neuronal Response to Simultaneous and Sequential Multi-Site Synaptic Stimulation

“…al. from experimental measurement and a detailed 3D reconstruction of a layer 2/3 pyramidal cell in a 3-5 week old Sprague-Dawley rat 7,8 (see figure 1). We used the same parameters, in particular for the AMPA (2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid) and NMDA (N-methyl-D-aspartate) neurotransmitter receptors.…”

“…In this section, two spatial patterns are studied; the first involves stimulation at multiple sites along the length of a single dendritic branch, and the second, for comparison, uses the same number of stimulation sites split evenly between two dendritic branches of similar morphological properties. We patterned our approach from the work by Branco et al 7,8 , which was based on sequential stimulation of excitatory synapses at 6ms time interval between synapses to study dendritic discrimination of temporal input sequences in cortical neurons. In this work, however, we study the effect of simultaneous (0 ms interval) as compared to sequential (1 to 8 ms interval) stimulation of multiple excitatory synapses distributed on one or two branches.…”

“…The difference in membrane depolarization lifetimes and summation between the two spatial patterns of stimulation is largely due to NMDA channel-related nonlinearities, which have a role in many spatial integration effects such as the integration gradient discussed by Branco and Hausser 7 . NMDA channels will activate preferentially at more depolarized membrane potentials 9 .…”