Signaling cascades underlying two different forms of LTP in hippocampus

Long-term potentiation (LTP) is an activity-dependent strengthening of excitatory synaptic efficacy that is considered to be a cellular model for learning & memory. LTP occurs at many types of synapses throughout the CNS. For example, in the hippocampus two distinct forms of LTP have been identified. These are the NMDAR-dependent LTP at the CA1 synapses and NMDAR-independent LTP at mossy fiber synapses. NMDAR-dependent LTP is induced by a transient increase in postsynaptic Ca2+. The processes required for the activation of NMDARs are thought to involve several protein kinases. For example, the activities of NMDAR channels are regulated by the tyrosine kinase Src and protein kinase C (PKC). However, the roles of Src kinase and mGluR-coupled PKC signaling pathways in the induction of the CA1 form of LTP have not been determined. I found here that the inhibition of Src kinase in CA1 pyramidal cells blocked LTP induction. Conversely directly activating Src in the postsynaptic neuron enhanced excitatory synaptic responses, occluding LTP induced by tetanus. Src-induced enhancement of AMPAR-mediated synaptic responses required both raised [Ca2+]i, and NMDARs. Thus Src activation is necessary and sufficient for inducing LTP, and may act by upregulating NMDARs. Another protein kinase, PKC, plays a more selective role in LTP. PKC is coupled to a metabotropic glutamate receptor, mGluR5, which is found predominantly in the CA1 postsynaptic neurons. CA1 neurons from mGluR5-deficient mice showed a complete loss of the NMDAR-mediated component of LTP (LTPNMDA), but normal LTP of the AMPAR-mediated component (LTPAMPA). Furthermore, the LTPNMDA deficit in mGluR5 mutant mice could be rescued by stimulating PKC. The results suggest that PKC couples mGluR5 to NMDAR potentiation during LTP, and this signaling mechanism is distinct from LTPAMPA. In mossy fiber-CA3 synapses, however, the induction of LTP arises from the increase in presynaptic glutamate release. The postsynaptic NMDAR plays no role in these events. I show here for the first time that the dietary depletion of bouton Zn2+ in the hippocampal slice, or with membrane-permeable Zn2+ chelators, following treatment, leads to deficits in the induction of LTP at Zn2+-containing mossy fiber-CA3 synapses. The Zn2+ effect was selective since no change was found in LTP at two-non-Zn2+-containing synapses, including commisural fiber-CA3 and Schaffer collateral-CA1 pathways. The impaired LTP at mossy fiber synapses was rescued by Zn2+ supplementation. Bath application of the membrane-impermeable Zn2+ chelator, Ca2+EDTA, had no effect on LTP. Our results indicated that presynaptically localized Zn2+ is specifically required for LTP induction at mossy fiber input into CA3 neurons. In summary, it is known that the process of LTP induction at the excitatory synapses in the hippocampus is carried out by ligand-gated ion channels and signaling molecules, which are clustered together. Two forms of LTP are induced by different cellular signaling cascades, even though the end result is an increase in synaptic efficacy. I have shown here that each of these two signaling molecules (Src kinas and mGluR-coupled PKC) reveals a distinct target component in LTP. Which of them, if any, are involved in learning and memory remains to be determined.