SHARED CALCIUM SIGNALING PATHWAYS IN THE INDUCTION OF LONG-TERM POTENTIATION AND SYNAPTIC DISINHIBITION IN CA1 PYRAMIDAL CELL DENDRITES

1. Calcium signaling pathways were examined in the induction of long-t erm synaptic disinhibition following tetanization. Effects of tetaniza tion on gamma-aminobutyric acid-A (GABA(A))-receptor-mediated inhibito ry responses were measured and compared with excitatory responses unde r experimental conditions previously used for examining induction mech anisms of N-methyl-D-aspartate (NMDA)-dependent long-term potentiation (LTP). Intracellular recordings were performed in current-clamp and d iscontinuous single-electrode voltage-clamp (dSEVC) modes in CA1 pyram idal cell apical dendrites in hippocampal slices of adult guinea pigs with the use of sharp electrodes. Test pulses and tetanic stimuli were applied to the Schaffer collateral fibers in stratum radiatum. 2. Und er standard control conditions [3 M KAc in the recording pipette and a rtificial cerebrospinal fluid as extracellular solution], tetanization -induced sustained increases of excitatory responses were accompanied by marked decreases of parameters of GABA(A) mediated synaptic inhibit ion: at 40 min after tetanization [posttetanus 40 (PT 40)], orthodromi cally evoked excitatory postsynaptic potential (EPSP) peak amplitudes were on average 195 +/- 15% (mean +/- SE) and excitatory postsynaptic currents (EPSCs) were 166 +/- 10% of pretetanus controls. Peak amplitu des of orthodromically evoked inhibitory postsynaptic potentials (IPSC s) were 30 +/- 5% and inhibitory postsynaptic currents (IPSCs) were 21 +/- 4% at PT 40. Synaptic GABA(A) conductances (measured as chord con ductances) were reduced to 22 +/- 4% at PT 40. Iontophoretic GABA(A) r esponses measured as conductance changes were 28 +/- 4% of pretetanus controls at PT 40. 3. A role of NMDA receptors in induction of long-te rm synaptic disinhibition was tested by preventing NMDA receptor activ ation 1) by pharmacological means and 2) by holding the membrane clamp ed at -80 mV (in dSEVC) during tetanization. In the presence of the NM DA-receptor antagonist D-2-amino-5-phosphonopentanoic acid (D-APS) (10 -40 mu M), orthodromically evoked EPSP amplitudes were 107 +/- 9%, EPS Cs were 104 +/- 6%, GABA(A)-mediated IPSPs were 88 +/- 8%, IPSCs were 97 +/- 8%, synaptic GABA(A) conductances were 84 +/- 9%, and iontophor etic GABA(A) conductances were 102 +/- 13% at PT 40. In recordings in which the dendritic membrane potential was clamped at -80 mV during te tanization, orthodromically evoked peak amplitudes of EPSPs were 105 /- 11%, EPSCs were 102 +/- 8, IPSPs were 103 +/- 4%, IPSCs were 102 +/ - 5%, GABA(A) chord conductances were 101 +/- 9%, and iontophoreticall y evoked GABA(A) conduc tances were 105 +/- 5% at PT 40. 4. In recordi ngs in which the intracellular pipette was preloaded with the Ca2+ che lator 1,2-bis (2-aminophenoxy) ethane-N,N,N'N''-tetraacetic acid (BAPT A) (5 mM), long-term changes of synaptic transmission (increases of ex citation, decreases of synaptic inhibition) were prevented. At PT 40, EPSP peak amplitudes were 93 +/- 7%, EPSCs were 115 +/- 6%, IPSPs were 115 +/- 9%, IPSCs were 117 +/- 8%, and synaptic GABAA conductances we re 108 +/- 17%. Iontophoretic conductances at PT 40 were 109 +/- 9% ov er pretetanus controls when recorded with BAPTA-containing electrodes. 5. In recordings in which the intracellular pipette was preloaded wit h cypermethrin, a potent and selective inhibitor of phosphatase 2B, re spective long-term changes of synaptic transmission (increases of exci tation, decreases of synaptic inhibition) were prevented. At PT 40, EP SP peak amplitudes were 98 +/- 6%, EPSCs were 105 +/- 10%, IPSPs were 99 +/- 5%, IPSCs were 104 +/- 7%, synaptic GABA(A) conductances were 9 7 +/- 6% and iontophoretic GABA(A) conductances were 113 +/- 18% over pretetanus controls in cypermethrin-containing recordings. 6. In concl usion, the data presented demonstrate shared cellular pathways in the induction of both LTP and long-term synaptic disinhibition in apical d endrites of CA1 pyramidal cells after tetanization of the Schaffer col laterals. The close temporal long-term correlation between potentiatio n of excitatory synaptic responses and decreases of inhibitory synapti c responses under various experimental conditions provides evidence fo r the notion of synaptic disinhibition contributing to NMDA-dependent pyramidal cell LTP in CA1.