A-Kinase anchoring protein-calcineurin signaling in long-term depression of GABAergic synapses
Résumé
The postsynaptic scaffolding A-kinase anchoring protein 79/150 (AKAP79/150) signaling complex regulates excitatory synaptic transmission and strength through tethering protein kinase A (PKA), PKC, and calcineurin (CaN) to the postsynaptic densities of neurons (Sanderson and Dell'Acqua, 2011), but its role in inhibitory synaptictransmission and plasticity is unknown. Using immunofluorescence and whole-cell patch-clamp recording in rat midbrain slices, we show that activation of postsynaptic D2 -like family of dopamine (DA) receptor in the ventral tegmental area (VTA) induces long-term depression (LTD) of GABAergic synapses on DA neurons through an inositol triphosphate receptor-mediated local rise in postsynaptic Ca2 and CaN activation accompanied by PKA inhibition, which requires AKAP150 as a bridging signaling molecule. Our data also illuminate a requirement for a clathrin-mediated internalization of GABAA receptors in expression of LTDGABA. Moreover, disruption of AKAP-PKA anchoring does not affect glutamatergic synapses onto DA neurons, suggesting that the PKA-AKAP-CaN complex is uniquely situated at GABAA receptor synapses in VTA DA neurons to regulate plasticity associated with GABAA receptors. Drug-induced modulation of GABAergic plasticity in the VTA through such novel signaling mechanisms has the potential to persistently alter the output of individual DA neurons and of the VTA, which may contribute to the reinforcing or addictive properties of drugs of abuse.