Developmental and molecular contributions to contextual fear memory emergence in mice

Cognitive impairment is a common phenotype of neurodevelopmental disorders, but how these deficits arise remains elusive. Determining the onset of discrete cognitive capabilities facilitates studies in probing mechanisms underlying their emergence. The present study analyzed the emergence of contextual fear memory persistence (7-day memory retention) and remote memory (30-day memory retention). There was a rapid transition from postnatal day (P) 20 to P21, in which memory persistence emerged in C57Bl/6J male and female mice. Remote memory was present at P23, but expression was not robust compared to pubertal and adult mice. To address a potential molecular mechanism, the present study examined the MET receptor tyrosine kinase (MET), which when deleted results in fear memory deficits in adult mice and regulates timing of critical period in the visual cortex, positioning it as a regulator for onset of contextual fear memory. Sustaining Met past the normal window of peak cortical expression or deleting Met did not alter the timing of emergence of persistence or remote memory capabilities. However, failure to exhibit fear memory occurred by P90 in mice with reduction or deletion of Met. Remarkably, the number of FOS-expressing infragranular neurons in medial prefrontal cortex (mPFC) did not increase with contextual conditioning at P35 but exhibited enhanced activation at P90. Additionally, MET-expressing neurons were preferentially recruited at P90 compared to P35 during fear memory expression. The studies demonstrate a developmental profile of contextual fear memory capabilities. Further, developmental disruption of Met leads to a delayed functional deficit that arises in adulthood.