DENDRITIC CA2+ 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 Schaffer collaterals at a low frequency, induces Ca2+-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 Ca2+ 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 (100 mu M) or MK-801 (10 mu M). 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 mu M) greatly reduced Ca2+ 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 mu M) or L-aspartate-beta-hydroxamate (50-100 mu M), as well as protein kinase C (PKC) inhibitors (sphingosine, 20 mu M; RO-31-8220, 0.2 mu M; or calphostin C, 2 mu M) also blocked LTP(k). Ca2+ transients were unaffected by r-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 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 Ca2+ directly into the dendritic spines. (C) 1994 Wiley-Liss, Inc.