The hippocampus of the mammalian brain, and particularly the dentate regions with its various inter-connections, are now recognized as playing key roles in both normal and pathological brain functions. The dentate gyrus, as the primary """"""""relay"""""""" for cortical input to the hippocampus, processes information critical to complex behaviors such as learning and memory. The activity and integrity of dentate neuronal populations may also set the level of excitability in the limbic system; maximal activation of dentate neurons facilitates spread of seizure activity, and dentate cell loss and/or axonal reconnectivity has been implicated in various animal models of epileptogenesis as well as in human epilepsy. Finally, studies of the connectivity and receptor populations of hippocampus have begun to implicate this limbic structure in a variety of issues relevant to affective disorders. Given these roles, it seems particularly important to elucidate the local connections of the hippocampal/dentate region and to examine its responses to modulatory substances. Over the past several years, we have attempted to characterize the properties and connectivities of some of the hippocampal interneuron populations. We propose to continue that analysis, with a particular focus on the pathways of interaction between the dentate and pyramidal cell regions. Our work has suggested that far from being a simple relay between entorhinal cortex and Ammon's horn, the dentate gurus has complex circuitry and a large number of cell types with unique characteristics. These observations add to studies from other laboratories which show the dentate gurus to be one among the """"""""hot spots"""""""" in the brain for receptors to potential modulatory substances. Changes in circulating steroid hormone levels has been shown to affect the integrity of the granule cells and their targets in CA3 neurotrophic factors and their receptors have now been found in these neurons; and mRNAs for a variety of factors can be altered as a function of electrical activities. Despite these findings, relatively little is known about how neuromodulatory substances, such as hormones or neurotrophins, affect dentate function. We propose to continue our elucidation of hippocampal circuitry, and to examine the direct affects of steroid hormones, neurotrophins and other potential modulatory substances on granule cells, and on granule cell synaptic transmission to dentate hilar and CA3 pyramidal cells. We will focus on circuits and drug actions that are likely to be significant for tissue plasticity, excitability, and viability. Electrophysiological recording and optical imaging, complimented by electron microscopy and immunocytochemistry, will be employed in these attempts to shed some light on the pathways of information transfer through the dentate, and on the processes by which that transfer can be modulated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS018895-18
Application #
6139468
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Fureman, Brandy E
Project Start
1983-01-01
Project End
2000-12-31
Budget Start
2000-01-01
Budget End
2000-12-31
Support Year
18
Fiscal Year
2000
Total Cost
$302,924
Indirect Cost
Name
University of Washington
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Kinoshita, Yoshito; Wenzel, H Jurgen; Kinoshita, Chizuru et al. (2012) Acute, but reversible, kainic acid-induced DNA damage in hippocampal CA1 pyramidal cells of p53-deficient mice. Epilepsia 53 Suppl 1:125-33
Knight, Leena S; Wenzel, H Jurgen; Schwartzkroin, Philip A (2012) Inhibition and interneuron distribution in the dentate gyrus of p35 knockout mice. Epilepsia 53 Suppl 1:161-70
Wenzel, H Jurgen; Tamse, Catherine T; Schwartzkroin, Philip A (2007) Dentate development in organotypic hippocampal slice cultures from p35 knockout mice. Dev Neurosci 29:99-112
Tschuluun, Naranzogt; Wenzel, H Jurgen; Schwartzkroin, Philip A (2007) Irradiation exacerbates cortical cytopathology in the Eker rat model of tuberous sclerosis complex, but does not induce hyperexcitability. Epilepsy Res 73:53-64
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Patel, Leena S; Wenzel, H Jurgen; Schwartzkroin, Philip A (2004) Physiological and morphological characterization of dentate granule cells in the p35 knock-out mouse hippocampus: evidence for an epileptic circuit. J Neurosci 24:9005-14
Lopantsev, V; Wenzel, H J; Cole, T B et al. (2003) Lack of vesicular zinc in mossy fibers does not affect synaptic excitability of CA3 pyramidal cells in zinc transporter 3 knockout mice. Neuroscience 116:237-48
Lopantsev, Valeri; Tempel, Bruce L; Schwartzkroin, Philip A (2003) Hyperexcitability of CA3 pyramidal cells in mice lacking the potassium channel subunit Kv1.1. Epilepsia 44:1506-12
Lopantsev, V; Schwartzkroin, P A (2001) GABA(A)-dependent chloride influx modulates reversal potential of GABA(B)-mediated IPSPs in hippocampal pyramidal cells. J Neurophysiol 85:2381-7

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