Jeffrey C. Magee - US grants

The general objective of this research proposal is to establish the role that voltage-gated ion channels located within dendritic arborizations have in determining the fundamental functions of neurons. A first step towards this objective is to establish exactly which types of voltage- gated ion channels are present in neuronal dendrites. This project will characterize the properties and distribution of dendritic voltage-gated K+ and hyperpolarization-activated (Ih) channels. Furthermore, the role that one of these channel populations (Ih channels) has in determining the basic electrical properties of CA1 dendrites will be directly investigated. Single K+ and Ih channel activity will be recorded directly from the dendrites of hippocampal CA1 pyramidal neurons in order to rigorously describe their biophysical and pharmacological properties. Simultaneous dendritic and somatic whole-cell recordings will be used to investigate dendritic ih channel function. The information attained from these studies will vastly improve our understanding of the physiological signals that are generated in and propagate through neuronal dendrites. Furthermore, a more complete understanding of neuronal membrane excitability will aid in determining the basic mechanisms of such neuronal diseases as epilepsy, alzheimers disease and neurogenic hypertension.

The long-range goal of this research project is to determine the fundamental mechanisms of information processing in central neurons. Most neurons of the mammalian CNS receive information through synaptic input that is located predominately within dendritic arborizations. It is here, in the dendrites, that thousands of excitatory and inhibitory synaptic inputs are blended together to form a coherent output response (this is known as dendritic integration). The morphology and active membrane properties of neuronal dendrites, therefore, play a very important role in the processing of incoming synaptic activity. Because synaptic input is widely spread across dendritic arborizations, the type of processing performed by the dendrites can vary dramatically as a function of the exact location of the synapse. This potentially large location-dependent synaptic variability has been shown to have detrimental effects on the processing capabilities of neurons. We sought to investigate the role that dendritic voltage-gated ion channels might have in reducing location-dependent synaptic variability. Several lines of preliminary evidence indicate that there is, contrary to theoretical expectations, minimal location-dependence to the individual components of dendritic integration (unitary EPSP amplitude, spatial summation and temporal summation). Furthermore we have preliminarily observed that the properties of the dendrites are responsible for this lack of location- dependence. Finally we have begun to show that by reducing the intrinsic location-dependence of dendritic processing the active properties of the dendrites improve the functional capabilities of CA1 pyramidal neurons. Thus, the central hypotheses to be tested is: dendritic ion channels reduce the location-dependence of synaptic input in hippocampal CA1 pyramidal neurons, improving their computational properties. The proposed studies will provide a more thorough understanding of the mechanisms involved in the integration of synaptic activity within dendrites and will therefore fundamentally advance our understanding of neuronal function.

[unreadable] DESCRIPTION (provided by applicant): The general objectives of this research proposal are to establish the mechanisms that control the dendritic processing of incoming synaptic information. In most CNS neurons, incoming synaptic inputs are widely distributed across dendritic arborizations that are both morphologically and electrically complicated and it is in these dendrites that tens of thousands of excitatory and inhibitory synaptic inputs are blended together to generate a coherent output response. In hippocampal CA1 pyramidal neurons, 85% of excitatory synaptic input is received by radial oblique dendrites. These are relatively short, small diameter secondary branches off the main dendrite trunk whose morphology suggests they might provide a favorable site for highly non-linear forms of synaptic processing. At present very little is known about the active properties of these dendrites or of the properties of the synapses that are formed on them. We propose to test the central hypotheses that: specific properties of oblique dendrites and the synapses formed on them provide CA1 neurons with multiple modes of processing synaptic input. The key players in determining the form of synaptic integration in these cells should be both the spatio-temporal aspects of the input itself and the availability of the voltage-gated ion channels within the obliques. We have designed experiments using a variety of dendritic whole-cell patch-clamp and advanced optical recording techniques to determine 1) the types and properties of voltage-gated ion channels located in these branches, 2) the properties of the synaptic inputs to the branches 3) precisely how synaptic input and active channels interact to shape integration within the branches and 4) how physiologically-relevant channel modulation can produce different forms of synaptic processing, all the while trying to relate the findings to the naturally occurring functional states of the hippocampus. The information produced by these experiments should provide us with a greater understanding of how information processing proceeds in central neurons and therefore a more fundamental understanding of both normal and pathological brain functioning. [unreadable] [unreadable]