Dendritic Ca2+ accumulations and metabotropic glutamate receptor activation associated with an n‐methyl‐d‐aspartate receptor‐independent long‐term potentiation in hippocampal CA1 neurons

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Abstract
Bathing hippocampal slices in the potassium channel blocker tetraethylammonium (TEA), while stimulating the Schafer collaterals at a low frequency, induces Ca2+ ‐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 (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 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 μM) 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 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 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.

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