Regulatory role and molecular interactions of a cell-surface heparan sulfate proteoglycan (N-syndecan) in hippocampal long-term potentiation

The cellular mechanisms responsible for synaptic plasticity involve interac tions between neurons and the extracellular matrix. Heparan sulfates (HSs) constitute a group of glycosaminoglycans that accumulate in the beta-amyloi d deposits in Alzheimer's disease and influence the development of neuron-t arget contacts by interacting with other cell surface and matrix molecules. However, the contribution of HSs to brain function is unknown. We found th at HSs play a crucial role in long-term potentiation (LTP), a finding that is consistent with the idea that converging molecular mechanisms are used i n the development of neuron-target contacts and in activity-induced synapti c plasticity in adults. Enzymatic cleavage of HS by heparitinase as well as addition of soluble heparin-type carbohydrates prevented expression of LTP in response to 100 Hz/1 sec stimulation of Schaffer collaterals in rat hip pocampal slices, A prominent carrier protein for the type of glycans implic ated in LTP regulation in the adult hippocampus was identified as N-syndeca n (syndecan-3), a transmembrane proteoglycan that was expressed at the proc esses of the CA1 pyramidal neurons in an activity-dependent manner, Additio n of soluble N-syndecan into the CAI dendritic area prevented tetanus-induc ed LTP. A major substrate of src-type kinases, cortactin (p80/85), and the tyrosine kinase fyn copurified with N-syndecan from hippocampus. Moreover, association of both cortactin and fyn to N-syndecan was rapidly increased a fter induction of LTP. N-syndecan may thus act as an important regulator in the activity-dependent modulation of neuronal connectivity by transmitting signals between extracellular heparin-binding factors and the fyn signalin g pathway.