N-methyl-D-aspartate receptor activation increases cAMP levels and voltage-gated Ca2+ channel activity in area CA1 of hippocampus.

Abstract

Tetanic stimulation of the Schaffer collateral inputs into area CA1 of the hippocampus causes N-methyl-Daspartate (NMDA) receptor activation, an effect that contributes to the induction of long-term potentiation (LTP) in this region. The present studies demonstrate that LTP-inducing tetanic stimulation in rat hippocampal area CA1 elicited increased levels of cAMP. The elevation of cAMP was blocked by the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV). Bath application of NMDA also resulted in an increase in cAMP in CA1, an effect that was blocked by both APV and removal of extracellular Ca2+. These frndings suggest that activation of NMDA receptors elicits a Ca2+-dependent increase in cAMP, and taken together with the data from tetanic stimulation, suggest that NMDA-receptor-mediated increases in cAMP could play a role in the induction of LTP in area CAL. One role for cAMP may be to increase Ca2+ influx through voltage-gated Ca21 channels, as it was observed that application of either Long-term potentiation of synaptic transmission (LTP) is a robust form of synaptic plasticity that is a strong candidate mechanism for learning and memory in the mammalian brain (for reviews, see refs. 1 and 2). The induction of the most commonly studied form of LTP in area CA1 of the hippocampus requires activation of N-methyl-D-aspartate (NMDA) receptors (3, 4). NMDA receptor activation allows the influx of Ca2+ into neurons, an effect that has been causally linked to the induction of LTP (5-8). The biochemical sequelae of the NMDA-receptor-mediated Ca2+ influx, however, are not well characterized. Available evidence suggests that the activation of Ca2+-dependent protein kinases contributes to the induction of LTP (9-12). Ca2+ is a pleuripotent second messenger, and many biochemical effects of Ca2' are well documented in the central nervous system, including activation, through calmodulin, ofadenylyl cyclase (13,14). In the experiments reported here, we tested the hypothesis that NMDA receptor activation increases cAMP in area CA1 of the hippocampus and that a physiological consequence of increased cAMP is an increase in the activity of voltage-gated Ca2+ channels. (1) in the CA1 region were monitored for 20 min to assure a stable baseline. Tetanic stimulation consisted of three one-s trains of stimuli (100 Hz) every 5 s at the minimum stimulus current needed to elicit a maximal population excitatory postsynaptic potential (EPSP). This stimulus was sufficient to induce LTP in >90%o of slices (20 of 22). LTP was defined as a 20% or greater increase in initial EPSP slope, or in initial experiments it was defined as a 30% or greater increase in population spike amplitude. When present, DL-2-amino-5-phosphonovaleric acid (APV) was 50 ,AM in the bath, a concentration that was found to block LTP induced by this stimulus paradigm (n = 6). MATERIALS AND METHODSMeasurement of cAMP. Slices were allowed to adjust to the recording chamber for 1.5-2 hr to allow cAMP levels to stabilize (15). Slices were removed fr...

In Vivo Protection against NMDA-induced Neurodegeneration by MK-801 and Nimodipine: Combined Therapy and Temporal Course of Protection

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