Ca2+-calmodulin signalling pathway up-regulates gaba synaptic transmission through cytoskeleton-mediated mechanisms

We investigated the role of calcium (Ca2+)/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(A)R)-gated inhibitory postsynaptic currents (IPSCs) and to perfuse intracellularly modulators in the presence of glutamate receptor antagonists. GABA(A)R-gated IPSCs were enhanced by the postsynaptic infusions of adenophostin (1 muM), a potent agonist of inositol-1,4,5-triphosphate receptor (IP3R) that induces Ca2+ 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 muM). Moreover, the postsynaptic infusion of Ca2+-CaM (40/10 muM) enhanced both evoked and spontaneous GABA(A)R-gated IPSCs. The enhancement was attenuated by co-infusing 100 muM CaM-KII(281-301), an autoinhibitory peptide of CaM-dependent protein kinases. These results indicate that postsynaptic Ca2+-CaM signaling pathways essentially enhance GABAergic synaptic transmission. In the investigation of synaptic targets for the enhancement, we found that IP3R agonist-enhanced GABAAR-gated IPSCs were attenuated by co-infusing colchicine (30 muM), vincristine (3 muM) or cytochalasin D (1 muM) that inhibits tubulin or actin polymerization, implying that actin filament and microtubules are involved. We conclude that postsynaptic Ca2+-CaM signaling pathways strengthen the function of GABAergic synapses via a cytoskeleton-mediated mechanism, probably the recruitment of receptors in the postsynaptic membrane. (C) 2004 IBRO. Published by Elsevier Ltd. All rights reserved.