title: Dendritic Ca2+ accumulations and metabotropic glutamate receptor activation associated with an N-methyl-D-aspartate receptor-independent long-term potentiation in hippocampal CA1 neurons.
abstract: Bathing hippocampal slices in the potassium channel blocker tetraethylammonium (TEA), while stimulating the Schaffer collaterals at a low frequency, induces Ca(2+)-dependent, N-methyl-D-aspartate (NMDA) receptor-independent long-term potentiation of synaptic transmission (LTPk) in CA1 neurons. We have combined ratio imaging of fura-2 and mag-fura-5 in hippocampal CA1 neurons with intracellular and field recordings to evaluate postsynaptic Ca2+ changes that occur in the induction of LTPk. Test stimuli were applied at 0.05 Hz to stratum radiatum in the presence of the NMDA receptor antagonists D,L-2-amino-5-phosphonovaleric acid (100 microM) or MK-801 (10 microM). During TEA exposure (15-25 mM; 10 min), cells fired prolonged action potentials both spontaneously and in response to test stimuli resulting in transient, micromolar Ca2+ accumulations in both somata and dendrites. The initial EPSP slope, measured 60 min after TEA wash-out, was potentiated to approximately 200% of control. The Ca2+ channel blocker nimodipine (10 microM) greatly reduced Ca2+ transients in both magnitude and duration and prevented LTPk induction. Pretreatment of slices with compounds that block metabotropic glutamate receptor (mGluR)-stimulated phosphoinositide hydrolysis, L-2-amino-3-phosphonopropionic acid (L-AP3, 50-200 microM) or L-aspartate-beta-hydroxamate (50-100 microM), as well as protein kinase C (PKC) inhibitors (sphingosine, 20 microM; RO-31-8220, 0.2 microM; or calphostin C, 2 microM) also blocked LTPk. Ca2+ transients were unaffected by L-AP3 or RO-31-8220. These findings suggest that Ca2+ influx through voltage-gated channels and co-activation of PKC by mGluRs are both necessary for induction of LTPk. Activation of mGluRs must also occur in NMDA receptor-dependent induction paradigms, but is possibly of lesser importance owing to the much greater gating of Ca2+ directly into the dendritic spines.
authors.affiliation: Roche Institute of Molecular Biology, Roche Research Center, Nutley, New Jersey 07110.
authors.forename: J J
authors.initials: JJ
authors.lastname: Petrozzino
authors.forename: J A
authors.initials: JA
authors.lastname: Connor
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003712:Dendrites / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D006168:Guinea Pigs; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017774:Long-Term Potentiation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009553:Nimodipine / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000494:pharmacology
chemical_list: D015221:Potassium Channels; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D013757:Tetraethylammonium Compounds; D009553:Nimodipine; D019789:Tetraethylammonium; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D011493:Protein Kinase C; D002118:Calcium