'Synaptic tagging' and 'cross-tagging' and related associative reinforcement processes of functional plasticity as the cellular basis for memory formation.

We focus on new properties of cellular and network processes of memory formation involving 'synaptic tagging' and 'cross-tagging' during long-term potentiation (LTP) and long-term depression (LTD) as well as associative heterosynaptic interactions, the latter of which are characterized by a time-window of about 1h. About 20 years ago we showed for the first time that the maintenance of LTP, like memory storage, depends on intact protein synthesis and thus consists of at least two temporal phases. Later, similar properties for LTD were shown by our own and other laboratories. Here we describe the requirements for the induction of the transient early-LTP/LTD and of the protein synthesis-dependent late-LTP/LTD. Late-LTP/LTD depend on the associative activation of heterosynaptic inputs, i.e. the synergistic activation of glutamatergic and modulatory reinforcing inputs within specific, effective time-windows during their induction. The induction of late-LTP/LTD is characterized by novel, late-associative properties such as 'synaptic tagging', 'cross-tagging' and 'late-associative reinforcement'. All of these phenomena require the associative setting of synaptic tags as well as the availability of plasticity-related proteins (PRPs) and they are restricted to functional dendritic compartments, in general. 'Synaptic tagging' guarantees input specificity, 'cross-tagging' determines the interaction between LTP and LTD in a neuron, and thus both are required for the specific processing of afferent signals for the establishment of late-LTP/LTD. 'Late-associative reinforcement' describes a process where early-LTP/LTD by the co-activation of modulatory inputs can be transformed into late-LTP/LTD in activated synapses where a tag is set. Recent experiments in the freely moving rat revealed a number of modulatory brain structures involved in the transformation of early-plasticity events into long-lasting ones. Further to this, we have characterized time-windows and activation patterns to be effective in the reinforcement process. Studies using a combined electrophysiological and behavioural approach revealed the physiological relevance of these reinforcement processes, which is also supported by fMRI studies in humans, which led to the hypothesis outlined here on cellular and system memory-formation by late-associative heterosynaptic interactions at the cellular level during functional plasticity events.