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

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.

Targeting PSD95/nNOS by ZL006 alleviates social isolation-induced heightened attack behavior in mice

“…In this study, a single dose of ZL006, a small-molecule inhibitor of PSD95/nNOS, attenuated escalation of attack behavior in the resident–intruder test at a dose that did not affect locomotor activity. To our knowledge, this is the first study to demonstrate that targeting PSD95/nNOS with ZL006 attenuates attack behavior induced by SI, thereby adding to the evidence for ZL006 as a potential treatment for various neurological disorders (Cai et al 2018b ; Doucet et al 2013 ; Li et al 2018 ; Qin et al 2019 ). Notably, we demonstrated that the effect of ZL006 on attack behavior was mediated via suppression of production of NO.…”

Activation of α7 nicotinic acetylcholine receptor ameliorates HIV-associated neurology and neuropathology

“… 98 Therapeutic approaches have been proposed to disrupt PSD-95/NMDAR complex to ameliorate pathological changes. 99–101 Meanwhile, our results showed increased PSD-95 expression was closely associated with improved learning and memory and locomotor activity. It is possible that increased PSD-95 serves as a compensatory mechanism for its loss in formation of abnormal complexes and to enhance its synaptic function, as evidenced in studies in which increased PSD-95 correlates with its protective effects in Alzheimer's disease and Parkinson's disease animal models.…”

Hippocampal overexpression of NOS1AP promotes endophenotypes related to mental disorders

“…We and others have previously emphasized the potential for targeting the nNOS/PSD-95 interaction for the pharmacological treatment of schizophrenia, depression, and other mental disorders [ 1 , 14 , 78 , 79 ]. The findings from the present study support this assertion and indicate a potential for directly targeting (i.e.…”