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Development and assessment of clinically relevant drugs for disruption of fear memory reconsolidation in models of post-traumatic stress disorder

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posted on 2024-04-16, 02:59 authored by Sanket RautSanket Raut

Background:
Evidence suggests that memory storage is dynamic. Long-term consolidated memories are updated with new significant experience. Retrieval of memory reactivates the memory trace to induce a state of instability (labilization) which requires restabilization through a process known as reconsolidation. Inhibition of reconsolidation by pharmacological interventions can lead to disruption of fear memories and may have therapeutic implications for post-traumatic stress disorder (PTSD) which is characterized by persistence of fear memory. Propranolol, sirolimus and mifepristone have been studied previously for disruption of fear memory reconsolidation albeit with mixed results and no drug has yet been approved for memory reconsolidation therapy for PTSD. This suggests that other pharmacological targets need to be explored to disrupt fear memory reconsolidation.
Molecular mechanisms of fear memory reconsolidation involve ERK/MAPK pathway in lateral amygdala. MEK inhibitors like U0126 and SL327, which block the ERK/MAPK pathway, have been previously shown to disrupt fear memory and its reconsolidation; however, they are not clinically translatable. The current thesis describes a research program designed to first assess current clinical evidence formally for propranolol in PTSD and secondly, using animal models with predictive validity, to perform pre-clinical assessment of the clinically relevant MEK inhibitor, mirdametinib, which completed phase 2 clinical trial for cancer, for memory reconsolidation therapy in post-traumatic stress disorder.
Method:
The current thesis includes one narrative review, one systematic review and meta?analysis and six experimental studies which address 1) the evidence for propranolol on the modification of trauma memory reconsolidation in PTSD patients and need to test new drug targets and memory labilization strategies 2) effect of mirdametinib on reconsolidation of auditory fear memory in C57BL/6 mice 3) role of prediction error on effect of mirdametinib on reconsolidation of auditory fear memory; 4) effect of mirdametinib on phosphorylated ERK/MAPK (pERK) expressing neurons in lateral amygdala (LA) 5) effect of mirdametinib on fear memory in absence of retrieval 6) effect of mirdametinib on spatial memory and spontaneous locomotor activity 7) the need to combine pre-reactivation D-cycloserine with post-reactivation mirdametinib to disrupt the reconsolidation of strong auditory fear memory and the impact of combined D-cycloserine and mirdametinib administration on pERK expression in LA.
We used auditory fear conditioning paradigm to test the effect of systemic mirdametinib on fear memory reconsolidation, and alterations for prediction error, in C57BL/6 mice. Effect of mirdametinib on pERK expression was studied using quantitative immunocytochemistry. Barnes maze and open field test were used to study the effect on spatial memory and spontaneous locomotor activity.
Results:
The systematic review and meta-analysis identified that at present there is not enough evidence to recommend use of propranolol for disruption of trauma memory in PTSD. Propranolol did not significantly reduce the PTSD symptoms or measures of physiological responding except for heart rate. The need to employ strategies like prediction error and administration of D?cycloserine to labilize traumatic memories were identified.
In pre-clinical studies mirdametinib alone did not disrupt fear memory reconsolidation. However, when combined with prediction error, mirdametinib disrupted reconsolidation of fear memory in mice. The effect was comparable to positive control SL327. Next, we confirmed the effect of mirdametinib on fear memory and showed also that it reduced the number of neurons expressing pERK in the LA. The effect of mirdametinib was specific to fear memory reconsolidation as its administration in absence of memory reactivation failed to disrupt fear memory. Moreover, mirdametinib did not affect general memory processes like spatial memory or influence spontaneous locomotor activity.
Next, we showed that mirdametinib disrupted the weak fear memory (1 x CS-US pairing) but did not affect strong fear memory (3 x CS-US pairing), indicating the difficulty in destabilization of strong fear memories. We addressed this differential effect of mirdametinib by systemic administration of the NMDA partial agonist D-cycloserine (DCS) before memory reactivation. We found DCS was able to destabilize memory and consequently mirdametinib when combined with DCS disrupted strong fear memories. Finally, we show changes in pERK expressing neurons in LA using micro-topographic mapping following administration of mirdametinib and DCS.
Conclusion:
New drugs strategies to disrupt fear memory reconsolidation are needed for PTSD. Propranolol, the most studied drug was found not to be effective in disrupting PTSD trauma memories and improving PTSD outcomes as demonstrated here by systematic review and meta-analysis suggesting that alternate targets need to be explored. We have identified and tested a new translatable MEK inhibitor, mirdametinib. Results of pre-clinical behavioral experiments and anatomical changes in pERK expression in LA suggests that mirdametinib crosses blood brain barrier and disrupts memory and thus could be developed for neuropsychiatric indications. The results also demonstrate the important role of prediction error in labilization of fear memory. Moreover, the results suggest the utility of combining DCS to labilize strong memories. These results demonstrate therapeutic approaches to disrupt persistent fear memories as seen in PTSD. Based on data from these experiments future clinical studies can investigate combining therapy to reactivate trauma memories, including prediction error and pre-recall DCS, followed by mirdametinib to disrupt reconsolidation of trauma memories in PTSD patients.

History

Sub-type

  • PhD Thesis

Pagination

xxiii. 219 pages

Department/School

School of Psychological Sciences

Publisher

University of Tasmania

Event title

Graduation

Date of Event (Start Date)

2023-04-28

Rights statement

Copyright 2023 the author

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