Abstract

Long-lasting activity-dependent alterations in the strength of synaptic connections are thought to be essential substrates of memory. Long-term potentiation (LTP) of synaptic transmission has been actively studied, while long-term depression (LTD) of synapse strength much less so. Prolonged low-frequency synaptic stimulation can elicit robust sLTD of synaptic strength. Our previous studies suggest that sLTD consists of multiple, distinct cascades, one dependent on the actions of the intercellular messenger nitric oxide (NO) that can act on presynaptic terminals, and a second due to postsynaptic, NO-independent mechanisms. We have discovered a chemical means of inducing LTD (cLTD) that appears to isolate presynaptic LTD mechanisms. cLTD requires the simultaneous production of cyclic GMP and inhibition of cyclic AMP-dependent protein kinase, and activates a NO-dependent, presynaptic cascade contribution to stimulus-induced sLTD. The proposed studies will employ electrophysiological recording, biochemical and two-photon confocal fluorescence imaging techniques in in vitro hippocampal slices to answer the following questions: (1) Are sLTD and cLTD associated with presynaptic alterations in vesicular transmitter release? (2) What biochemical cascades underlie the presynaptic portion of stimulus-induced sLTD? (3) Does cLTD share mechanisms with NMDA or group I mGluR receptor-dependent LTD?, and (4) Are presynaptic calcium channels and/or vesicle release apparatus proteins targets for phosphorylation or dephosphorylation underlying sLTD and cLTD? Better understanding of LTD impacts many clinical issues. There is a hypothetical role for LTD in memory processing, and impairments in LTD may contribute to pathologies of memory storage such as Alzheimer's Disease. LTD-like dampening of neuronal excitation could be effective in preventing epileptic seizures and reduce excitotoxic neuronal injury. Such potential applications await a detailed understanding of the cellular neurochemistry underlying LTD.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS044421-02S1
Application #
6938280
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Talley, Edmund M
Project Start
2003-04-01
Project End
2007-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
2
Fiscal Year
2004
Total Cost
$82,000
Indirect Cost

  Institution

Name
New York Medical College
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
041907486
City
Valhalla
State
NY
Country
United States
Zip Code
10595

  Publications

Moskal, Joseph R; Burgdorf, Jeffrey S; Stanton, Patric K et al. (2017) The Development of Rapastinel (Formerly GLYX-13); A Rapid Acting and Long Lasting Antidepressant. Curr Neuropharmacol 15:47-56
Burgdorf, Jeffrey; Colechio, Elizabeth M; Ghoreishi-Haack, Nayereh et al. (2017) IGFBP2 Produces Rapid-Acting and Long-Lasting Effects in Rat Models of Posttraumatic Stress Disorder via a Novel Mechanism Associated with Structural Plasticity. Int J Neuropsychopharmacol 20:476-484
Burgdorf, Jeffrey; Colechio, Elizabeth M; Stanton, Patric et al. (2017) Positive Emotional Learning Induces Resilience to Depression: A Role for NMDA Receptor-mediated Synaptic Plasticity. Curr Neuropharmacol 15:3-10
Burgdorf, Jeffrey; Kroes, Roger A; Zhang, Xiao-lei et al. (2015) Rapastinel (GLYX-13) has therapeutic potential for the treatment of post-traumatic stress disorder: Characterization of a NMDA receptor-mediated metaplasticity process in the medial prefrontal cortex of rats. Behav Brain Res 294:177-85
Burgdorf, J; Zhang, X-L; Weiss, C et al. (2015) The long-lasting antidepressant effects of rapastinel (GLYX-13) are associated with a metaplasticity process in the medial prefrontal cortex and hippocampus. Neuroscience 308:202-11
Burgdorf, Jeffrey; Zhang, Xiao-lei; Colechio, Elizabeth M et al. (2015) Insulin-Like Growth Factor I Produces an Antidepressant-Like Effect and Elicits N-Methyl-D-Aspartate Receptor Independent Long-Term Potentiation of Synaptic Transmission in Medial Prefrontal Cortex and Hippocampus. Int J Neuropsychopharmacol 19:
Moskal, Joseph R; Burch, Ronald; Burgdorf, Jeffrey S et al. (2014) GLYX-13, an NMDA receptor glycine site functional partial agonist enhances cognition and produces antidepressant effects without the psychotomimetic side effects of NMDA receptor antagonists. Expert Opin Investig Drugs 23:243-54
Upreti, Chirag; Zhang, Xiao-Lei; Alford, Simon et al. (2013) Role of presynaptic metabotropic glutamate receptors in the induction of long-term synaptic plasticity of vesicular release. Neuropharmacology 66:31-9
Zhang, Xiao-lei; Pöschel, Beatrice; Faul, Christian et al. (2013) Essential role for synaptopodin in dendritic spine plasticity of the developing hippocampus. J Neurosci 33:12510-8
Burgdorf, Jeffrey; Zhang, Xiao-lei; Nicholson, Katherine L et al. (2013) GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects. Neuropsychopharmacology 38:729-42

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