Microcircuit level effects of MEK inhibitors on threat memory disruption

Memories formed as a result of threatening events can have debilitating effects on quality of life. Solutions to treat these memories are limited to behavioural therapies and non-specific pharmacotherapy. Neither behavioural therapies nor current pharmacotherapy have a lasting effect on memories and quality of life. Pavlovian threat (fear) conditioning results in changes to neural plasticity in the amygdala, specifically in the dorsal subdivision of the lateral amygdala (LAd), where plastic changes to the microcircuitry occur. Plastic changes include increases in the number of neurons expressing pMAPK/ERK activity and changes to the structure and shape of the neuron including changes to dendritic spines. Modifications to plasticity occur during both initial memory consolidation and subsequent reconsolidation of fear memories. MEK inhibitors, upstream inhibitors of pMAPK/ERK activity are known to block pMAPK/ERK activity when administered both intra brain and systemically and also block initial consolidation and reconsolidation of threat memories. However the precise effect of MEK inhibitors on different sub-regional microcircuitry is unknown. Our initial data suggests that the number of neurons in the LAd expressing pMAPK/ERK is significantly reduced (by up to 90%) following a systemic injection of the MEK inhibitor SL327. In conclusion these data provide initial microcircuit level analysis of the effects of MEK inhibitor on neural microcircuits underlying threat memories.