Cellular/MolecularDevelopmental Changes in AMPA and Kainate Receptor-Mediated Quantal Transmission at ThalamocorticalSynapses in the Barrel CortexNeil J. Bannister,1Timothy A. Benke,2Jack Mellor,1Helen Scott,1Esra Gu¨rdal,1,3John W. Crabtree,1andJohn T. R. Isaac1,41Medical Research Council Centre for Synaptic Plasticity, Department of Anatomy, University of Bristol, Bristol BS8 1TD, United Kingdom,2Department ofPediatrics, University of Colorado Health Sciences Center, Denver, Colorado 80262,3Department of Anatomy, Marmara University School of Medicine,Haydarpasa 34668, Istanbul, Turkey, and4National Institute of Neurological Disorders and Stroke, National Institutes Health, Bethesda, Maryland 20892During the first week of life, there is a shift from kainate to AMPA receptor-mediated thalamocortical transmission in layer IV barrelcortex. However, the mechanisms underlying this change and the differential properties of AMPA and kainate receptor-mediated trans-mission remain essentially unexplored. To investigate this, we studied the quantal properties of AMPA and kainate receptor-mediatedtransmission using strontium-evoked miniature EPSCs. AMPA and kainate receptor-mediated transmission exhibited very differentquantal properties but were never coactivated by a single quantum of transmitter, indicating complete segregation to different synapseswithin the thalamocortical input. Nonstationary fluctuation analysis showed that synaptic AMPA receptors exhibited a range of single-channel conductance (␥) and a strong negative correlation between␥and functional channel number, indicating that these two param-eters are reciprocally regulated at thalamocortical synapses. We obtained the first estimate of␥for synaptic kainate receptors (⬍2 pS),and this primarily accounted for the small quantal size of kainate receptor-mediated transmission. Developmentally, the quantal con-tribution to transmission of AMPA receptors increased and that of kainate receptors decreased. No changes in AMPA or kainate quantalamplitude or in AMPA receptor␥were observed, demonstrating that the developmental change was attributable to a decrease in thenumber of kainate synapses and an increase in the number of AMPA synapses contributing to transmission. Therefore, we demonstratefundamental differences in the quantal properties for these two types of synapse. Thus, the developmental switch in transmission willdramatically alter information transfer at thalamocortical inputs to layer IV.Key words: glutamate; synaptic transmission; layer IV; neocortex; miniature EPSC; nonstationary fluctuation analysisIntroductionFast excitatory synaptic transmission in the mammalian CNS ismediated predominately by the AMPA, NMDA, and kainate typeionotropic glutamate receptors (Hollmann and Heinemann,1994). Kainate receptors are widely expressed in the mammalianbrain, but their physiological roles are poorly understood becauseof a lack, until recently, of selective ligands and genetic tools.Studies so far have indicated roles for kainate receptors in long-term potentiation (LTP), in regulating circuit excitability, and inepilepsy (Frerking and Nicoll, 2000; Schmitz et al., 2001; Kull-mann, 2001; Lerma et al., 2001; Lerma, 2003).At developing thalamocortical inputs in barrel cortex, bothpresynaptic and postsynaptic kainate receptors are activated bysynaptically released glutamate (Kidd and Isaac, 1999, 2001; Kiddet al., 2002). The kainate receptor-mediated EPSC evoked at thisinput exhibits slow kinetics, similar to that observed at othersynapses (Castillo et al., 1997; Vignes and Collingridge, 1997;Cossart et al., 1998; Frerking et al., 1998; Li and Rogawski, 1998;Li et al., 1999; Bureau et al., 2000). The thalamocortical kainatereceptor-mediated EPSC can be readily separated from theAMPA receptor (AMPAR)-mediated component of transmis-sion both pharmacologically and kinetically (Kidd and Isaac,1999, 2001). An interesting feature of transmission in barrel cor-tex is that studies so far suggest that AMPA and kainate receptorsdo not colocalize at the same synapses (Kidd and Isaac, 1999).During development, the relative contribution of the kainatereceptor-mediated component to transmission decreases, andthis is paralleled by an increase in the AMPA receptor-mediatedcomponent, a change that can also be rapidly produced byNMDA receptor-dependent LTP (Kidd and Isaac, 1999).The synaptic mechanisms underlying the developmentalchange from kainate to AMPA receptor-mediated transmissionare essentially unexplored. Moreover, what determines the dif-ferential properties of AMPA and kainate receptor-mediatedtransmission at this input are unclear. To investigate these issues,Received Feb. 27, 2004; revised April 19, 2005; accepted April 19, 2005.This work was supported by the Wellcome Trust (J.M., J.T.R.I.), National Institutes of Health Grant NS 41267(T.A.B.), andthe NationalInstitute ofNeurological Disordersand Stroke(J.T.R.I.). We thankJosh Lawrenceand ChrisMcBain fortheir advice onthe voltage-jump experimentsand the Universityof Bristol MedicalResearch Council CellImaging Centre.Correspondence should be addressed to John Isaac, National Institute of Neurological Disorders and Stroke/National Institutes of Health, 35 Convent Drive, Bethesda, MD 20892. E-mail: [email protected]:10.1523/JNEUROSCI.0827-05.2005Copyright © 2005 Society for Neuroscience 0270-6474/05/255259-13$15.00/0The Journal of Neuroscience, May 25, 2005 • 25(21):5259–5271 • 5259we studied the quantal and single-channel properties of kainateand AMPA receptor-mediated transmission at thalamocorticalsynapses onto layer IV neurons in developing barrel cortex [post-natal day 2 (P2) to P9], using Sr2⫹-evoked miniature EPSCs(mEPSCs). We find that, although both kainate and AMPA re-ceptors mediate quantal transmission, they do so completely in-dependently and have very different quantal and single-channelproperties. Developmentally, there is a decrease in the quantalcontribution of kainate receptor-mediated transmission and areciprocal increase in the quantal contribution of AMPAreceptor-mediated transmission. No developmental change isobserved in the quantal size of these two types of transmission orin AMPA receptor single-channel properties. These findings pro-vide the first detailed comparison of the quantal and single-channel properties of AMPA and kainate receptor-mediatedtransmission in developing neocortex. Our findings indicate thatkainate and AMPA