The how and why for multiple forms of hippocampal LTP.

Activity-induced Long-Term Potentiation (LTP)-characterized as it is by rapid induction, synapse specificity, and remarkable persistence-has long been considered a primary substrate for memory encoding. There has however been considerable debate about the cellular mechanisms responsible for producing the potentiated state. It seems that much of the confusion can be traced to an implicit assumption that there is a single form of stable potentiation. However, features of LTP in Schaffer-commissural (SC) input to CA1 and perforant path projections from entorhinal cortex to dentate gyrus (DG), show that different nodes of the hippocampal circuit express different types of LTP and that distinctions can be found even within the same population of synapses. For the SC system, brief theta burst stimulation (TBS) elicits LTP that is expressed by an expansion of the spine, postsynaptic density and associated AMPA receptor pool, and stabilized by reorganization of the actin cytoskeleton. Both sexes employ these mechanisms but females rely on locally synthesized estrogen and synaptic estrogen receptors to set processes in motion whereas males more heavily rely on metabotropic NMDA receptor signaling. Extended theta burst trains, high frequency stimulation (HFS), and spike timing paradigms engage mechanisms of LTP induction that differ from those produced by the minimal TBS. And an even more radical form of potentiation is expressed at lateral perforant path (LPP) connections with the DG. In this case, LTP is triggered postsynaptically but expressed presynaptically by increased transmitter release with an endocannabinoid providing the requisite retrograde messenger. These sex- and region-specific differences in plasticity have meaningful consequences for episodic memory encoding and vulnerability to neurological insults.