The regulatory role of proheparanase in synaptic plasticity at the hippocampus

Abstract

Perineuronal heparan sulfate (HS) moieties are implicated in the control of the open-state of ion channels for the maintenance of synaptic strength. We hypothesize that neuronal mechanisms modulate peri-synaptic HS level and as a result play roles in the regulation of synaptic strength and plasticity. To address this, basal synaptic strength and long-term changes in synaptic potentiation in the Schaffer collateral pathway of the rat hippocampus were assessed in relation to strategies that perturb peri-synaptic HS. Heparitinase treatment of hippocampal slices resulted in dose-dependent attenuation of long-term potentiation (LTP) in correlation with loss of perineuronal HS moieties but no change in basal synaptic strength. Our finding of heparanase expression at the CA1 hippocampal neurons led us to test if heparanase is the mammalian counterpart of heparitinase in the regulation of synaptic strength/plasticity. We asked therefore if neuronal heparanase is secreted as the pro-form or the active form. Following phorbol ester stimulation of hippocampal neurons in culture, Western blot analysis of both the pericellular and cytoplasmic fractions revealed pericellular proheparanase accompanied by increase in enzymatically active heparanase in the cytoplasmic fraction. Treatment of the cultures with exogenous proheparanase triggered co-internalization of both cell-surface HS and AMPA-type glutamate receptors. With use of calcium-imaging technique, proheparanase treatment was found to block glutamate-induced calcium influx of the hippocampal neurons in culture. Consistent with these findings, treatment of hippocampal slices with exogenous proheparanase resulted in declines in both basal synaptic strength and LTP. Taken together, our findings suggest activity-dependent secretion of neuronal proheparanase to peri-synaptic HS-sites and subsequent re-setting of AMPA receptor level at the synapse as a novel mechanism for the regulation of synaptic plasticity. [HKRGC GRF 774608]