Maintenance of memory by negative feedback of synaptic protein elimination: modeling KIBRA–PKMζ dynamics in LTP

Long-term activity-dependent modifications of synaptic strength are a cellular substrate of learning and memory, but how long-lasting memory could be based on synaptic proteins that rapidly degrade and diffuse is unknown. Most current theories depend on molecular positive-feedback loops. Recent experiments, however, reveal that interactions between kidney brain protein (KIBRA) and PKMζ downregulate the proteins’ degradation and maintains late-phase long-term synaptic plasticity (LTP) and long-term memory, motivating an alternative model based on negative feedback at the level of protein elimination. Here we compare positive- and negative-feedback models generally and explore biophysical models based specifically on KIBRA–PKMζ interaction. The biophysical theory predicts LTP/memory maintenance by complexes of cooperative KIBRA–PKMζ heteromers.