Diversity of neuropsin (KLK8)-dependent synaptic associativity in the hippocampal pyramidal neuron

Abstract

Activity-dependent synaptic plasticity is widely accepted to provide a cellular basis for learning and memory. Synaptic associativity could be involved in activity-dependent synaptic plasticity, because it distinguishes between local mechanisms of synaptic tags and cell-wide mechanisms that are responsible for the synthesis of plasticity-related proteins. We report that a plasticity-related serine protease, neuropsin, is involved in the tag-setting process during long-term potentiation (LTP) at basal and apical dendritic inputs. Neuropsin is involved in synaptic associativity during LTP at apical dendritic inputs via integrin β1 and CaMKII signalling. Thus, neuropsin is a candidate molecule for LTP-specific tag-setting and could regulate the transformation of early to late LTP during synaptic associativity. These findings may provide the understanding of the regulation of synaptic associativity as complex information-processing systems. Abstract Hippocampal early (E-) long-term potentiation (LTP) and long-term depression (LTD) elicited by a weak stimulus normally fades within 90 min. Late (L-) LTP and LTD elicited by strong stimuli continue for >180 min and require new protein synthesis to persist. If a strong tetanus is applied once to synaptic inputs, even a weak tetanus applied to another synaptic input can evoke persistent LTP. A synaptic tag is hypothesized to enable the capture of newly synthesized synaptic molecules. This process, referred to as synaptic tagging, is found between not only the same processes (i.e. E- and L-LTP; E- and L-LTD) but also between different processes (i.e. E-LTP and L-LTD; E-LTD and L-LTP) induced at two independent synaptic inputs (cross-tagging). However, the mechanisms of synaptic tag setting remain unclear. In our previous study, we found that synaptic associativity in the hippocampal Schaffer collateral pathway depended on neuropsin (kallikrein-related peptidase 8 or KLK8), a plasticity-related extracellular protease. In the present study, we investigated how neuropsin participates in synaptic tagging and cross-tagging. We report that neuropsin is involved in synaptic tagging during LTP at basal and apical dendritic inputs. Moreover, neuropsin is involved in synaptic tagging and cross-tagging during LTP at apical dendritic inputs via integrin β1 and calcium/calmodulin-dependent protein kinase II signalling. Thus, neuropsin is a candidate molecule for the LTP-specific tag setting and regulates the transformation of E- to L-LTP during both synaptic tagging and cross-tagging. © 2011 The Authors. Journal compilation © 2011 The Physiological Society.