Adenosine receptor blockade reveals N-methyl-D-aspartate receptor- and voltage-sensitive dendritic spikes in rat hippocampal CA1 pyramidal cells in vitro

The present study was done to determine the possible effects of endogenous adenosine, present in the extracellular fluid of the hippocampal slice, on pyramidal cells in the CA1 region using intracellular recording techniques. Administration of 5 microM of the adenosine receptor antagonist, 8-sulfophenyltheophylline (n=11), induced a depolarization (2.6+/-0.4 mV, mean+/-S.E.M.) with an increase in input resistance (6.7+/-2.1%) in pyramidal cells, and increased the amplitude of the excitatory postsynaptic potentials elicited by stimulation of Schaffer collateral afferents; 50 microM 8-sulfophenyltheophylline (n=68) produced a similar depolarization (3.4+/-1.7 mV) and an increase in input resistance (26+/-3.0%), but also produced spontaneous, synchronized giant excitatory postsynaptic potentials which could generate bursts of spikes. These effects lasted more than 10 min after washout. In the presence of 20 microM 6-cyano-7-nitro-quinoxaline-2,3-dione, a non-N-methyl-D-aspartate receptor antagonist, and 50 microM D-2-amino-5-phosphonovalerate, an N-methyl-D-aspartate receptor antagonist, 50 microM 8-sulfophenyltheophylline (n=4) induced only depolarization (3.1+/-1.3 mV) and an increase in input resistance (23+/-3.8%). In the presence of 20 microM 6-cyano-7-nitro-quinoxaline-2,3-dione only, 50 microM 8-sulfophenyltheophylline (n=7) induced not only the depolarization with an increase in input resistance, but also the occurrence of small-amplitude (11+/-5.6 mV), fast rising, all-or-none, voltage-sensitive spikes of 2-3 ms duration, which were attributed to a dendritic origin. The latency of these dendritic spikes in response to stimulation of Schaffer collateral afferents lasted up to 21 ms. These dendritic spikes could generate one or more action potentials, depending on the resting membrane potential and the frequency of the dendritic spikes. In the presence of 50 microM 8-sulfophenyltheophylline plus 20 microM 6-cyano-7-nitro-quinoxaline-2,3-dione, 50 microM D-2-amino-5-phosphonovalerate blocked the spontaneous dendritic spikes (n=4). In the presence of 5 microM 8-sulfophenyltheophylline, 200 microM N-methyl-D-aspartate (n=5) increased the occurrence of dendritic spikes.These data indicate that adenosine present in the extracellular fluid of the hippocampal slice tonically inhibits not only (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate-mediated synaptic transmission, but also voltage- and N-methyl-D-aspartate receptor-sensitive dendritic spikes. Endogenous adenosine acting on adenosine A(1) receptors is thus visualized as a control to prevent the genesis of synchronized giant excitatory postsynaptic potentials. In our experiments, blockade of this tonic activation of adenosine receptors appears to have altered the origins of action potentials and led to epileptiform firing in CA1 pyramidal cells.