Dendritic Ca 2+ accumulations and metabotropic glutamate receptor activation associated with an n‐methyl‐d‐aspartate receptor‐independent long‐term potentiation in hippocampal CA1 neurons

Bathing hippocampal slices in the potassium channel blocker tetraethylammonium (TEA), while stimulating the Schafer collaterals at a low frequency, induces Ca 2+ ‐dependent, N ‐methyl‐D‐aspartate (NMDA) receptor‐independent long‐term potentiation of synaptic transmission (LTP k ) 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 Ca 2+ changes that occur in the induction of LTP k . 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 (100μM) or MK‐801 (10μM). 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 Ca 2+ 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 Ca 2+ channel blocker nimodipine (10 μM) greatly reduced Ca 2+ transients in both magnitude and duration and prevented LTP k 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 μM) or L ‐aspartate‐β‐hydroxamate (50–100 μM), as well as protein kinase C (PKC) inhibitors (sphingosine, 20 μM; RO‐31‐8220, 0.2 μM; or calphostin C, 2 μM) also blocked LTP k . Ca 2+ transients were unaffected by L ‐AP3 or RO‐31‐8220. These findings suggest that Ca 2+ influx through voltage‐gated channels and co‐activation of PKC by mGluRs are both necessary for induction of LTP k . 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 Ca 2+ directly into the dendritic spines. © 1994 Wiley‐Liss, Inc.