Presynaptic inhibition of synaptic transmission in the rat hippocampus by activation of muscarinic receptors: involvement of presynaptic calcium influx

Modulation of presynaptic voltage‐dependent calcium channels (VDCCs) by muscarinic receptors at the CA3–CA1 synapse of rat hippocampal slices was investigated by using the calcium indicator fura‐2. Stimulation‐evoked presynaptic calcium transients ([Ca pre ] t ) and field excitatory postsynaptic potentials (fe.p.s.ps) were simultaneously recorded. The relationship between presynaptic calcium influx and synaptic transmission was studied. Activation of muscarinic receptors inhibited [Ca pre ] t , thereby reducing synaptic transmission. Carbachol (CCh, 10 μ M ) inhibited [Ca pre ] t by 35% and reduced fe.p.s.p. by 85%. The inhibition was completely antagonized by 1 μ M atropine. An approximate 4 th power relationship was found between presynaptic calcium influx and postsynaptic responses. Application of the N‐type VDCC‐blocking peptide toxin ω‐conotoxin GVIA (ω‐CTx GVIA, 1 μ M ) inhibited [Ca pre ] t and fe.p.s.ps by 21% and 49%, respectively, while the P/Q‐type VDCC blocker ω‐agatoxin IVA (ω‐Aga IVA, 1 μ M ) reduced [Ca pre ] t and fe.p.s.ps by 35% and 85%, respectively. Muscarinic receptor activation differentially inhibited distinct presynaptic VDCCs. ω‐CTx GVIA‐sensitive calcium channels were inhibited by muscarinic receptors, while ω‐Aga IVA‐sensitive channels were not. The percentage inhibition of ω‐CTx GVIA‐sensitive [Ca pre ] t was about 63%. Muscarinic receptors inhibited presynaptic VDCCs in a way similar to adenosine (Ad) receptors. The percentage inhibition of ω‐CTx GVIA‐sensitive [Ca pre ] t by Ad (100 μ M ) was about 59%. There was no significant inhibition of ω‐Aga IVA‐sensitive channels by Ad. The inhibitions of [Ca pre ] t by CCh and Ad were mutually occlusive. These results indicate that inhibition of synaptic transmission by muscarinic receptors is mainly the consequence of a reduction of the [Ca pre ] t due to inhibition of presynaptic VDCCs. British Journal of Pharmacology (1997) 122 , 511–519; doi: 10.1038/sj.bjp.0701400