Nelson Spruston - US grants

Nelson Spruston
IBN-9876032

The central nervous system (CNS) is made up of approximately 100 billion nerve cells. Most of these neurons communicate with one another at contact points called synapses. On one side of the synapse, the speaker (the presynaptic neuron) communicates via action potentials - electrical signals about 100 mV in amplitude and 1-2 ms in duration. On the other side, the listener (the postsynaptic neuron) interprets these signals arriving simultaneously from thousands of presynaptic neurons. This conversation is complicated by the fact that not all neurons speak the same language. Some neurons fire as few as a few action potentials per second; others fire as many as a thousand action potentials per second. Differences are also observed in the patterns of action potential firing. The biological underpinnings of action potential firing patterns are largely determined by pore-forming molecules called ion channels. A new avenue of research into the mechanisms responsible for variations in action potential firing patterns is to study the properties of ion channels located in different parts of the neuron. For example the axon, which generally forms the presynaptic side of the synapse, expresses different ion channels than the dendrites, which forms the postsynaptic side of the synapse. Here I propose to use new technology to study the properties of ion channels in the dendrites of neurons in an area of the brain called subiculum. This area is part of the hippocampus, which is involved in learning and memory. Neurons in the subiculum are known to generate clusters of action potentials called bursts. This pattern is very different than that of their nearest neighbors in the CA1 region of the hippocampus, which are morphologically similar, but cannot generate bursts of action potentials. I propose to perform experiments that will test the hypothesis that the bursting observed in subicular neurons is caused by specialized properties of sodium and/or potassium channels in the dendrites of these neurons. Using recently developed technology, the properties of channels in the dendrites of subicular neurons will be compared to those in CA1 neurons determined in previous and ongoing studies in my lab. Together with action potential recordings from dendrites, pharmacological manipulations, and computer modeling studies, I aim to elucidate the differences between subicular and CA1 neurons that are responsible for the very different action potential firing patterns in these two cell types. The proposal also contains an educational component designed to teach undergraduate students about the importance of neuronal specialization in the central nervous system, and the
biological mechanisms underlying neuronal diversity.

[unreadable] DESCRIPTION (provided by applicant): Neuronal circuits exhibit specialization at many levels; in particular, neuronal diversity and differences in connectivity are thought to be crucial. Significant advances have been made in understanding the types of plasticity that may contribute to learning and memory in the hippocampus, but much less has been discovered about how the circuit stores and extracts information. A key aspect of all circuit function is the diverse population of inhibitory interneurons, which differ in physiological properties, dendritic morphology and axon targeting. Understanding of circuit function can be significantly enhanced by capturing the complexity inherent in neuronal diversity and connectivity in detailed computer models of the system. Here we propose to study and model specific populations on interneurons in the hippocampus identified in BAG transgenic mice generated by the NINDS-Gensat project. We propose to record from identified neurons in these mice in order to determine their physiological properties. The recorded cells will also be stained so that dendritic morphology can be determined and quantified. Computational models will then be generated of the interneurons and pyramidal neurons to which they project for the purpose of making experimentally testable predictions concerning hippocampal circuit function. This is a collaborative project that brings together investigators, students, and postdocs to take a multidisciplinary approach to the study of hippocampal circuit function. The project has five specific aims: 1) Physiological investigation of hippocampal interneurons in BAG transgenic mice. 2) Anatomical investigation of hippocampal interneurons in BAG transgenic mice. 3) Studies of modulation of interneurons in BAG transgenic mice. 4) Modeling hippocampal interneurons from BAG transgenic mice. 5) Developing advanced computational methods for microcircuit modeling. The proposed work has important implications for several neurological disorders, including Alzheimer's disease, epilepsy, and schizophrenia. [unreadable] [unreadable] [unreadable]

This award will provide partial support for a new Gordon Research conference on the topic of Dendrites: Molecules, Structure and Function. Dendrites are the structures responsible for integrating synaptic inputs in almost all neurons and thus serve a critical role in information processing in the nervous system. The meeting will bring together researchers studying dendrites from different perspectives, including computational, molecular and cell biological, anatomical, and elctrophysiological. There is a specific emphasis on the role that dendrites play in synaptic plasticity. A range of new techniques has recently been applied to the study of the structure and function of dendrites, with a consequent increase in information about the structure and function of these essential components of neurons, and this conference will bring together many of the experts in the field to assimilate this new wealth of information. Topics to be covered include the molecular determinants of dendritic shape, the role that protein synthesis and molecular trafficking play in dendritic function, structural plasticity of dendrites, signal integration in dendrites, computational characteristics of dendrites, the role of dendrites in synaptic plasticity, dendrites as presynaptic elements, and the mechanisms governing intrinsic plasticity of dendrites. The conference is designed to facilitate interaction among graduate students, postdoctoral fellows, and more senior investigators. The funds requested are to be used to provide support for students and post-docs to attend the conference, and to encourage faculty from underrepresented groups to participate in the meeting by supporting their travel costs. A graduate symposium will also be held that is associated with the meeting. This symposium will provide a setting for these young scientists to present their data and discuss scientific developments in an environment that is less stressful and more nurturing than the main meeting itself. It will also provide a way for the participants to gain valuable background knowledge about the techniques and concepts presented in talks at the main meeting, which are expected to be both wide-ranging and at a relatively high level and thus quite demanding for graduate students.