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

L. P. Li, E. T. Dustrude, M. M. Haulcomb, A. R. Abreu, S. D. Fitz, P. L. Johnson, G. A. Thakur, A. I. Molosh, Y. Lai, A. Shekhar

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Article number155
JournalTranslational psychiatry
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Biological Psychiatry

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    Li, L. P., Dustrude, E. T., Haulcomb, M. M., Abreu, A. R., Fitz, S. D., Johnson, P. L., Thakur, G. A., Molosh, A. I., Lai, Y., & Shekhar, A. (2018). PSD95 and nNOS interaction as a novel molecular target to modulate conditioned fear: relevance to PTSD. Translational psychiatry, 8(1), [155]. https://doi.org/10.1038/s41398-018-0208-5