AKAP-CaN-NFATc3 signaling drives persistent inhibitory long-term potentiation

GABAergic inhibitory synaptic plasticity has critical roles in neuronal function, synaptic plasticity, and cognition. Activity-dependent alterations in gene expression are essential for generating long-term changes in inhibitory postsynaptic strength, yet the signaling mechanisms that drive inhibitory postsynaptic plasticity are not well understood. During an important form of inhibitory long-term potentiation (iLTP), NMDA receptor (NMDAR) activity promotes de novo synthesis of GABAA receptors (GABAARs) and the inhibitory scaffold, gephyrin, leading to persistent strengthening of inhibition. However, it remains unclear what activity-dependent signaling mechanisms control these changes in gene expression to maintain iLTP. In this study, we identify that activation of the transcription factor, nuclear-factor of activated T-cells (NFAT), and anchoring of the phosphatase, calcineurin (CaN), to A-kinase anchoring protein (AKAP79/150) are crucial in regulating long-term structural and functional GABAergic postsynaptic plasticity. Using short hairpin RNA (shRNA) to knock-down hippocampal NFAT isoform, NFATc3, we demonstrate its requirement for the synthesis of new inhibitory synaptic proteins, inhibitory synapse growth, and strengthening of synaptic currents during persistent iLTP. Additionally, using a knock-in mouse line containing a mutation in the CaN binding region of AKAP, we find that AKAP-CaN signaling lies upstream of NFATc3 activation and is required for increased inhibitory synapse clustering and synapse strengthening during iLTP via regulation of miRNA transcriptional activity and protein synthesis. Thus, we have identified an excitation-transcription coupling pathway that rapidly controls the synthesis of new inhibitory synaptic proteins and maintains persistent inhibitory synaptic plasticity, an essential process for memory formation and cognition in the brain.