Increasing Synaptic GluN2B levels within the Basal and Lateral Amygdala Enables the Modification of Strong Reconsolidation Resistant Fear Memories

de Solis, C. A.; Gonzalez, C. U.; Galdamez, M. A.; Perish, J. M.; Woodard, S. W.; Salinas, C. E.; Miller, J. N.; Elahi, H.; Pineda, O. H.; Oad, S.; Gatica de las Fuentes, S.; Owen, M. S.; Sandoval, A.; Holehonnur, R.; Ploski, J. E.

doi:10.1101/537142

bioRxiv · 10.1101/537142

Increasing Synaptic GluN2B levels within the Basal and Lateral Amygdala Enables the Modification of Strong Reconsolidation Resistant Fear Memories

de Solis, C. A.·Gonzalez, C. U.·Galdamez, M. A.·Perish, J. M.·Woodard, S. W.·Salinas, C. E.·Miller, J. N.·Elahi, H.·Pineda, O. H.·Oad, S.·Gatica de las Fuentes, S.·Owen, M. S.·Sandoval, A.·Holehonnur, R.·Ploski, J. E.

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Abstract

Reconsolidation disruption has been proposed as a method to attenuate pathological memories in disorders such as PTSD. However, studies from our group and others indicate that strong memories are resistant to becoming destabilized following reactivation, rendering them impervious to agents that disrupt the re-stabilization phase of reconsolidation. Thus, therapies designed to attenuate maladaptive memories by disrupting reconsolidation updating have not been adequately developed. We previously determined that animals possessing strong auditory fear memories, compared to animals with weaker fear memories, are associated with an enduring increase in the synaptic GluN2A/GluN2B ratio in neurons of the mouse basal and lateral amygdala (BLA). In this study, we determined whether increasing GluN2B levels within BLA excitatory neuronal synapses is sufficient to enable modification of strong fear memories via reconsolidation. To accomplish this, we utilized a combinatorial genetic strategy to express GluN2B or GluN2B(E1479Q) in excitatory neurons of the mouse BLA before or after fear memory consolidation. GluN2B(E1479Q) contains a point mutation that increases synaptic expression of the subunit by interfering with phosphorylation-driven endocytosis. At the time of memory retrieval, increasing synaptic GluN2B levels by expression of GluN2B(E1479Q), but not GluN2B(WT), enhanced the induction of reconsolidation rendering the strong fear memory modifiable. GluN2B(WT) or GluN2B(E1479Q) expression did not influence fear memory maintenance or extinction. Fear memory consolidation, however, was enhanced when GluN2B(E1479Q) was expressed in the BLA at the time of training. These findings indicate that enhancing GluN2B synaptic trafficking may provide a novel therapeutic strategy to enhance modification of pathological memories.

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de Solis, C. A., Gonzalez, C. U., Galdamez, M. A., Perish, J. M., Woodard, S. W., Salinas, C. E., Miller, J. N., Elahi, H., Pineda, O. H., Oad, S., Gatica de las Fuentes, S., Owen, M. S., Sandoval, A., Holehonnur, R., Ploski, J. E.. 2019-01-31. Increasing Synaptic GluN2B levels within the Basal and Lateral Amygdala Enables the Modification of Strong Reconsolidation Resistant Fear Memories. https://doi.org/10.1101/537142

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