THROMBOXANE A(2) AGONIST MODULATION OF EXCITATORY SYNAPTIC TRANSMISSION IN THE RAT HIPPOCAMPAL SLICE

1 The effects of the selective thromboxane A(2) (TXA(2)) receptor agon ist I-BOP on neuronal excitability and synaptic transmission were stud ied in the CA1 neurones of rat hippocampal slices by an intracellular recording technique. 2 Superfusion of I-BOP (0.5 mu M) resulted in a b iphasic change of the excitatory postsynaptic potential (e.p.s.p.), wh ich was blocked by pretreatment with SQ 29548, a specific antagonist o f TXA(2) receptors. The inhibitory phase of I-BOP on the e.p.s.p. was accompanied by a decrease in neuronal membrane input resistance. 3 The sensitivity of postsynaptic neurones to glutamate receptor agonists, lpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or N-me thyl-D-aspartate (NMDA), was unchanged by I-BOP (0.5 mu M) pretreatmen t. 4 Bath application of Ba2+ (0.5 mM) prevented both the I-BOP-induce d reduction of the neuronal membrane input resistance and the blockade of e.p.s.p. induced by I-BOP. 5 Intracellular dialysis of the hippoca mpal CA1 neurones with GDP (10 mM) significantly attenuated the I-BOP inhibition of e.p.s.p. and membrane input resistance. Incubation of th e slices with either pertussis toxin (PTX, 5 mu g ml(-1) for 12 h) or cholera toxin (CTX, 5 mu g ml(-1) for 12 h) did not affect the biphasi c action of I-BOP on the e.p.s.p. or the reduction of membrane input r esistance induced by I-BOP. 6 Pretreatment of the slices with the prot ein kinase C (PKC) inhibitor, NPC-15437 (20 mu M), abolished the bipha sic modulation by I-BOP (0.5 mu M) of the e.p.s.p. Intracellular appli cation of a specific PKC inhibitor, PKCI 19-36 (20 mu M), completely i nhibited the I-BOP reduction of e.p.s.p. The specific cyclic AMP-depen dent protein kinase (PKA) inhibitor, Rp-cyclic adenosine 3',5'-monopho sphate (Rp-cyclic AMPS, 25 mu M), had no effect on the I-BOP action. 7 In this study we have demonstrated, for the first time, the existence of functional TXA(2) receptors in the hippocampus which mediate the e ffects of a TXA(2) agonist on neuronal excitability and synaptic trans mission. Activation of the presynaptic TAX(2) receptors may stimulate the release of glutamate. Conversely, activation of postsynaptic TXA(2 ) receptors leads to inhibition of synaptic transmission resulting fro m a decrease in the membrane input resistance of the neurones. The pre - and postsynaptic actions of the TXA(2) agonist are both mediated by PTX- and CTX-insensitive G-protein-coupled activation of PKC pathways.