Ca 2+–calmodulin signalling pathway up-regulates GABA synaptic transmission through cytoskeleton-mediated mechanisms

Abstract

We investigated the role of calcium (Ca 2+)/calmodulin (CaM) signaling pathways in modulating GABA synaptic transmission at CA1 pyramidal neurons in hippocampal slices. Whole-cell pipettes were used to record type A GABA receptor (GABA AR)-gated inhibitory postsynaptic currents (IPSCs) and to perfuse intracellularly modulators in the presence of glutamate receptor antagonists. GABA AR-gated IPSCs were enhanced by the postsynaptic infusions of adenophostin (1 μM), a potent agonist of inositol-1,4,5-triphosphate receptor (IP 3R) that induces Ca 2+ release. The enhancement was blocked by co-infusing either 1,2-bis(2-aminophenoxy)-ethane- N, N, N′, N′-tetraacetic acid (10 mM) or CaM-binding peptide (100 μM). Moreover, the postsynaptic infusion of Ca 2+-CaM (40/10 μM) enhanced both evoked and spontaneous GABA AR-gated IPSCs. The enhancement was attenuated by co-infusing 100 μM CaM-KII(281–301), an autoinhibitory peptide of CaM-dependent protein kinases. These results indicate that postsynaptic Ca 2+-CaM signaling pathways essentially enhance GABAergic synaptic transmission. In the investigation of synaptic targets for the enhancement, we found that IP 3R agonist-enhanced GABA AR-gated IPSCs were attenuated by co-infusing colchicine (30 μM), vincristine (3 μM) or cytochalasin D (1 μM) that inhibits tubulin or actin polymerization, implying that actin filament and microtubules are involved. We conclude that postsynaptic Ca 2+-CaM signaling pathways strengthen the function of GABAergic synapses via a cytoskeleton-mediated mechanism, probably the recruitment of receptors in the postsynaptic membrane.