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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS046064-05A1
Application #
7267323
Study Section
Special Emphasis Panel (ZRG1-IFCN-B (03))
Program Officer
Liu, Yuan
Project Start
2002-09-30
Project End
2012-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
5
Fiscal Year
2007
Total Cost
$316,249
Indirect Cost
Name
Northwestern University at Chicago
Department
Physiology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Kim, Yujin; Hsu, Ching-Lung; Cembrowski, Mark S et al. (2015) Dendritic sodium spikes are required for long-term potentiation at distal synapses on hippocampal pyramidal neurons. Elife 4:
Menon, Vilas; Musial, Timothy F; Liu, Annie et al. (2013) Balanced synaptic impact via distance-dependent synapse distribution and complementary expression of AMPARs and NMDARs in hippocampal dendrites. Neuron 80:1451-63
Sheffield, Mark E J; Edgerton, Gabrielle B; Heuermann, Robert J et al. (2013) Mechanisms of retroaxonal barrage firing in hippocampal interneurons. J Physiol 591:4793-805
Harnett, Mark T; Makara, Judit K; Spruston, Nelson et al. (2012) Synaptic amplification by dendritic spines enhances input cooperativity. Nature 491:599-602
Sheffield, Mark E J; Best, Tyler K; Mensh, Brett D et al. (2011) Slow integration leads to persistent action potential firing in distal axons of coupled interneurons. Nat Neurosci 14:200-7
Menon, Vilas; Spruston, Nelson; Kath, William L (2009) A state-mutating genetic algorithm to design ion-channel models. Proc Natl Acad Sci U S A 106:16829-34
Katz, Yael; Menon, Vilas; Nicholson, Daniel A et al. (2009) Synapse distribution suggests a two-stage model of dendritic integration in CA1 pyramidal neurons. Neuron 63:171-7
Rempe, Michael J; Spruston, Nelson; Kath, William L et al. (2008) Compartmental neural simulations with spatial adaptivity. J Comput Neurosci 25:465-80
Spruston, Nelson (2008) Pyramidal neurons: dendritic structure and synaptic integration. Nat Rev Neurosci 9:206-21
Katz, Yael; Kath, William L; Spruston, Nelson et al. (2007) Coincidence detection of place and temporal context in a network model of spiking hippocampal neurons. PLoS Comput Biol 3:e234

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