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      PSD95 and nNOS interaction as a novel molecular target to modulate conditioned fear: relevance to PTSD

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          Abstract

          Stimulation of N-methyl-D-aspartic acid receptors (NMDARs) and the resulting increase of nitric oxide (NO) production are critical for fear memory formation. Following NMDAR activation, efficient production of NO requires linking the 95 kDa postsynaptic density protein (PSD95), a scaffolding protein to neuronal nitric oxide synthase (nNOS). A variety of previously studied NMDAR antagonists and NOS inhibitors can disrupt fear conditioning, but they also affect many other CNS functions such as motor activity, anxiety, and learning. We hypothesized that disrupting nNOS and PSD95 interaction in the amygdala, a critical site for fear memory formation, will reduce conditioned fear. Our results show that systemic treatment with ZL006, a compound that disrupts PSD95/nNOS binding, attenuates fear memory compared to its inactive isomer ZL007. Co-immunoprecipitation after fear conditioning showed a robust increase in the amygdala PSD95/nNOS binding, which was blocked by systemic pre-administration of ZL006. Treatment of amygdala slices with ZL006 also impaired long-term potentiation (LTP), a cellular signature of synaptic plasticity. Direct intra-amygdala infusion of ZL006 also attenuated conditioned fear. Finally, unlike NMDAR antagonist MK-801, ZL006 does not affect locomotion, social interaction, object recognition memory, and spatial memory. These findings support the hypothesis that disrupting the PSD95/nNOS interaction downstream of NMDARs selectively reduces fear memory, and highlights PSD95/nNOS interaction as a novel target for fear-related disorders, such as posttraumatic stress disorder.

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          Most cited references 52

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          Fear conditioning, synaptic plasticity and the amygdala: implications for posttraumatic stress disorder.

          Posttraumatic stress disorder (PTSD) is an anxiety disorder that can develop after a traumatic experience such as domestic violence, natural disasters or combat-related trauma. The cost of such disorders on society and the individual can be tremendous. In this article, we review how the neural circuitry implicated in PTSD in humans is related to the neural circuitry of fear. We then discuss how fear conditioning is a suitable model for studying the molecular mechanisms of the fear components that underlie PTSD, and the biology of fear conditioning with a particular focus on the brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB), GABAergic and glutamatergic ligand-receptor systems. We then summarize how such approaches might help to inform our understanding of PTSD and other stress-related disorders and provide insight to new pharmacological avenues of treatment of PTSD. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            Chronic stress impairs rat spatial memory on the Y maze, and this effect is blocked by tianeptine pretreatment.

            Chronic restraint stress causes significant dendritic atrophy of CA3 pyramidal neurons that reverts to baseline within a week. Therefore, the authors assessed the functional consequences of this atrophy quickly (within hours) using the Y maze. Experiments 1-3 demonstrated that rats relied on extrinsic, spatial cues located outside of the Y maze to determine arm location and that rats with hippocampal damage (through kainic acid, colchicine, or trimethyltin) had spatial memory impairments. After the Y maze was validated as a hippocampally relevant spatial task, Experiment 4 showed that chronic restraint stress impaired spatial memory performance on the Y maze when rats were tested the day after the last stress session and that tianeptine prevented the stress-induced spatial memory impairment. These data are consistent with the previously demonstrated ability of tianeptine to prevent chronic stress-induced atrophy of the CA3 dendrites.
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              Neuronal nitric oxide synthase: structure, subcellular localization, regulation, and clinical implications.

              Nitric oxide (NO), a free gaseous signaling molecule, is involved in the regulation of the cardiovascular, nervous and immune system. The neurotransmitter function of nitric oxide is dependent on dynamic regulation of its biosynthetic enzyme, nitric oxide synthase (NOS). There are three types of NOS, neuronal nitric oxide synthase (nNOS), endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS). Of the three NOS, we focus on nNOS in the present review. Brain nNOS exists in particulate and soluble forms and the differential subcellular localization of nNOS may contribute to its diverse functions. Proteins bearing PDZ domains can interact directly with the PDZ domain of nNOS, influencing the subcellular distribution and/or activity of the enzyme. During the past several years, an increasing number of reports have demonstrated the importance of nNOS in a variety of synaptic signaling events. nNOS has been implicated in modulating physiological functions such as learning, memory, and neurogenesis, as well as being involved in a number of human diseases. In this review we concentrate on recent findings regarding the structural features, subcellular localization and factors regulating nNOS function. In particular, we conclude with a section discussing the role of nNOS in a wide range of physiological and pathological conditions.
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                Author and article information

                Contributors
                +317-278-6969 , ashekhar@iu.edu
                Journal
                Transl Psychiatry
                Transl Psychiatry
                Translational Psychiatry
                Nature Publishing Group UK (London )
                2158-3188
                14 August 2018
                14 August 2018
                2018
                : 8
                Affiliations
                [1 ]ISNI 0000 0001 2287 3919, GRID grid.257413.6, Medical Neuroscience Graduate Program, , Indiana University School of Medicine, ; Indianapolis, IN USA
                [2 ]ISNI 0000 0001 2287 3919, GRID grid.257413.6, Stark Neurosciences Research Institute, , Indiana University School of Medicine, ; Indianapolis, IN USA
                [3 ]ISNI 0000 0001 2287 3919, GRID grid.257413.6, Department of Psychiatry, , Indiana University School of Medicine, ; Indianapolis, IN USA
                [4 ]Anagin Inc., Indiana Center for Biomedical Innovation, Indianapolis, IN USA
                [5 ]ISNI 0000 0001 2287 3919, GRID grid.257413.6, Department of Anatomy and Cell Biology, , Indiana University School of Medicine, ; Indianapolis, IN USA
                [6 ]ISNI 0000 0001 2173 3359, GRID grid.261112.7, Department of Pharmaceutical Sciences, , Northeastern University, ; Boston, MA USA
                [7 ]ISNI 0000 0001 0790 959X, GRID grid.411377.7, Gill Center for Biomolecular Science and Department of Psychological and Brain Sciences, , Indiana University Bloomington, ; Bloomington, IN USA
                [8 ]ISNI 0000 0001 2287 3919, GRID grid.257413.6, Indiana Clinical and Translational Sciences Institute, , Indiana University School of Medicine, ; Indianapolis, IN USA
                Article
                208
                10.1038/s41398-018-0208-5
                6092346
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/100000025, U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH);
                Award ID: R21MH104018
                Award ID: R43MH103936
                Award Recipient :
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                © The Author(s) 2018

                Clinical Psychology & Psychiatry

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