Post-translational synaptic protein modification as substrate for long-lasting, remote memory: an initial test

The current view of the molecular basis for information storage is that post-translational modification (PTM) of brain proteins is important for the early stages of memory storage and that protein synthesis is necessary for long-lasting memory. This view has been challenged by the proposal that PTM of synaptic proteins is the critical instructive mechanism underlying both recent as well as long-lasting memories (Routtenberg and Rekart, 2005). As an initial test, a broad spectrum serine/threonine kinase inhibitor (H-7) was delivered bilaterally to rat anterior cingulate cortex 1 h before a 3 week retention test of contextual fear conditioning. This significantly blocked 21-Day retention. In the second experiment evaluating extinction of a 21-Day remote memory, H-7 injected into mouse medial prefrontal cortex blocked fear extinction. As the H-7-induced impairment in 21-Day retention was indexed by a decrease in freezing, while the extinction blockade by no decrease in freezing, the results could not be ascribed to a direct effect of the drug on behavioral performance. This represents the first demonstration, to our knowledge, that PTM inhibition, here serine/threonine kinase activity, interferes with long-lasting memory, providing initial support for the PTM model.