The neocortex is the part of the brain that has expanded most dramatically in size and complexity in parallel with the development of human intellectual abilities. Here, countless thousands of pieces of information about our own bodies and the world around us are integrated and processed to generate perceptions and memories and to initiate appropriate responses. These pieces of information arrive from all over the nervous system as electrical signals. These electrical signals are transferred from one nerve cell, or neurone, to another via tiny chemical signals that in turn generate electrical and chemical events in each follower neurone. The receiving neurones are often very complex, in their shapes and in their electrical and chemical properties. Each one is made up of many different compartments into which information can be channelled. The properties of these different compartments, the way that events in them interact with events in other compartments and how they work together to transform the many different pieces of information that constantly bombard each neurone, into the output of that cell, is the subject of this project. We focus particularly on properties that are affected in neurological diseases such as the several different types of epilepsy, in some cases as the possible cause, in others as the brain?s response to another change or insult.

Technical Abstract:
Evidence for specificity in the properties of synaptic connections is growing, though few studies have examined this issue directly in the smaller dendritic branches of pyramidal cells. Fewer still have studied how the properties of postsynaptic dendritic compartments shape individual synaptic inputs and their summation with events from neighbouring synapses. Many different mechanisms contribute to dendritic properties; mechanisms that may be differentially expressed in different pyramidal cells, different dendrites and dendritic compartments.

We will test the hypothesis that each class of synaptic input to a given class of postsynaptic cell is distributed over a highly specific region of dendritic space that is homogeneous in its active and passive properties, involves only certain types of dendrites and is at a given electrotonic distance from the soma.

This project will compare the properties of two families of neocortical pyramidal cell dendrites, the apical oblique and the basal dendrites of layer 3 pyramidal cells and how their properties shape the synaptic inputs that impinge upon them. Inputs from layer 4 spiny cells selectively innervate the basal dendrites of layer 3 pyramids, while layer 3 inputs also innervate apical obliques. Calcium transients in the dendrite and voltage responses at the soma produced by the release of caged-glutamate onto different dendritic compartments will be recorded. These will be compared with responses to the glutamate released by the synaptic boutons of a single identified presynaptic neurone in paired recording experiments; the postsynaptic dendritic compartment(s) involved being identified by the close apposition of fluorescently labelled axon and dendrite and co-localised calcium signals. How voltage-gated K+ and cation-selective (HCN) ion channels modify glutamatergic inputs to different dendritic compartments will be explored with ion channel blockers and by comparison of wild type mice with mice lacking HCN or Kv4 channels. These data and 3D reconstructions of the layer 3 neurones will tune a detailed compartmental layer 3 pyramidal cell model and predictions eg. about summation tested experimentally.

How both pre- and post-synaptic GABAergic inhibition in these same dendritic compartments interacts with excitatory inputs will also be directly assessed. In one block of paired recording experiments, the effect of uncaging GABA at different positions relative to a synapse(s) from a single presynaptic excitatory cell will be studied. In the other, responses to glutamate uncaged at different positions along a dendrite will be challenged with the input from a single inhibitory interneurone innervating the same dendritic branch.