N-methyl-D-aspartate receptors (NMDARs) play critical roles in information processing and in the synaptic plasticity that underlies learning and memory. Depending upon the pattern of activation, NMDARs can promote long-term potentiation (LTP) or long-term synaptic depression (LTD), two leading candidates for synaptic memory mechanisms. When activated excessively, however, NMDARs can also cause several forms of neurodegeneration. We have observed that there are also conditions in which NMDAR activation produces no change in synaptic responses or neuronal injury, but impairs the ability to generate LTP. This NMDAR-mediated LTP inhibition is observed with low level activation of NMDARs, certain patterns of synaptic stimulation and exposure to sub-lethal stressful conditions (brief hypoxia and low glucose). Because of the role that synaptic plasticity plays in memory processing, this NMDAR-mediated LTP inhibition may be important for understanding the cognitive defects that accompany untimely NMDAR activation in neuropsychiatric disorders. In recent studies, we found that low level NMDAR activation promotes the production of GABA-enhancing neurosteroids in hippocampal pyramidal neurons and these neurosteroids play a key role in LTP inhibition. In this proposal, we will extend our work on NMDAR LTP inhibition by pursuing three aims: 1. To determine conditions under which NMDAR activation promotes neurosteroid production and how steroids contribute to LTP modulation;2. To determine signaling mechanisms underlying NMDAR-induced neurosteroid production;and 3. To determine the effects of NMDA and neurosteroids on GABAergic inhibition and the mechanisms underlying these effects. These studies will be conducted in the CA1 region of rat hippocampal slices, an area known to be important for memory processing. Our long-term goal is to identify ways to preserve and restore synaptic function in individuals with neuropsychiatric illnesses.

Public Health Relevance

Psychiatric disorders involve dysfunction in neural circuits underlying cognition, emotion and motivation. Although the biology of these disorders is poorly understood, the hippocampus has emerged as a major hub in several disorders and plays a critical role in brain systems involved in mental function and declarative memory formation. In these studies, we will examine mechanisms underlying hippocampal dysfunction in stressful conditions, including the role of neurosteroids. These studies have potential to shed new light on the role of the hippocampus in neuropsychiatric illnesses and to identify novel approaches to treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH077791-06A1
Application #
8313018
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Asanuma, Chiiko
Project Start
2006-07-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
6
Fiscal Year
2012
Total Cost
$435,015
Indirect Cost
$139,242
Name
Washington University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Mennerick, Steven; Taylor, Amanda A; Zorumski, Charles F (2014) Phosphatidylinositol 4,5-bisphosphate depletion fails to affect neurosteroid modulation of GABAA receptor function. Psychopharmacology (Berl) 231:3493-501
Stein, Liana Roberts; Wozniak, David F; Dearborn, Joshua T et al. (2014) Expression of Nampt in hippocampal and cortical excitatory neurons is critical for cognitive function. J Neurosci 34:5800-15
Linsenbardt, Andrew J; Taylor, Amanda; Emnett, Christine M et al. (2014) Different oxysterols have opposing actions at N-methyl-D-aspartate receptors. Neuropharmacology 85:232-42
Zorumski, Charles F; Mennerick, Steven; Izumi, Yukitoshi (2014) Acute and chronic effects of ethanol on learning-related synaptic plasticity. Alcohol 48:1-17
Purgert, Carolyn A; Izumi, Yukitoshi; Jong, Yuh-Jiin I et al. (2014) Intracellular mGluR5 can mediate synaptic plasticity in the hippocampus. J Neurosci 34:4589-98
Izumi, Yukitoshi; Zorumski, Charles F (2014) Metaplastic effects of subanesthetic ketamine on CA1 hippocampal function. Neuropharmacology 86:273-81
Wozniak, David F; Diggs-Andrews, Kelly A; Conyers, Sara et al. (2013) Motivational disturbances and effects of L-dopa administration in neurofibromatosis-1 model mice. PLoS One 8:e66024
Tokuda, Kazuhiro; Izumi, Yukitoshi; Zorumski, Charles F (2013) Locally-generated acetaldehyde is involved in ethanol-mediated LTP inhibition in the hippocampus. Neurosci Lett 537:40-3
Svrakic, Dragan M; Zorumski, Charles F; Svrakic, Nenad M et al. (2013) Risk architecture of schizophrenia: the role of epigenetics. Curr Opin Psychiatry 26:188-95
Zorumski, Charles F; Paul, Steven M; Izumi, Yukitoshi et al. (2013) Neurosteroids, stress and depression: potential therapeutic opportunities. Neurosci Biobehav Rev 37:109-22

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