Oligomer logic of memory molecules.

It has been 40 years since Francis Crick [1] noted the problem molecular turnover poses for maintaining memories and offered a general solution. The solution requires that the critical molecules must be replaced without altering the overall structure of the complex. It is timely then that Todd Sacktor's group [2] has identified critical intermolecular interactions that satisfy Crick's requirement. Sacktor's early work identified the continuously active kinase, protein kinase Mzeta (PKMzeta) as a critical molecule for maintaining localized postsynaptic AMPA receptors that support long-term potentiation (LTP) and memory. More recent work revealed that PKMzeta forms heterodimers with the scaffolding protein KIBRA (KIbra BRAin) and preventing dimerization erased both LTP and memory. Even so, dimers degrade too fast to support long-lasting memories. Based on biophysical modeling, Sacktor's group with Harel Shouval reasoned that if KIBRA-PKMzeta heterodimers interact to form oligomers (such as hexamers), they can survive molecular turnover because as a dimer degrades it can be replaced by another. AlphaFold 3 predicted a site where the small molecule inhibitor, zeta-stat, would bind and disrupt oligomer formation. If so, then infusing zeta-stat into the hippocampus should erase long-term memory. This predicted outcome was observed. Thus, Crick's solution has been achieved. Oligomers formed from KIBRA-PKMzeta dimers allow degraded individual molecules to be replaced one at a time while maintaining their overall structure. This permits a continuous presence of PKMzeta where it interacts with AMPA receptors (through GluA2 subunits) and other molecules to ensure long-term memories endure.