DHHC2-Mediated AKAP150 Palmitoylation Regulates Hippocampal Synaptic Plasticity and Fear Memory

Abstract Background A-kinase anchoring protein 79/150 (AKAP150) has been suggested to be involved in learning and memory, and synaptic plasticity in the hippocampus is closely associated with memory. However, its effect and underlying mechanisms have not yet been fully elucidated. Result Here, we show that there is a significant increase in global and AKAP150 palmitoylation level after high frequency stimulation (HFS). 2-bromopalmitic acid (2-BP), a palmitoylation inhibitor, attenuated the increased palmitoylation level of AKAP150, and abolished the increased interaction between AKAP150 and postsynaptic density protein 95 (PSD-95) induced by HFS. We also found that HFS increased the synaptic expression of protein kinase A (PKA), but not calcineurin (CaN), and the HFS-mediated high affinity binding of PKA to AKAP150 was reversed by 2-BP. Furthermore, the activity of DHHC2, an enzyme responsible for palmitoylation of AKAP150, was upregulated after HFS, and DHHC2 knockdown decreased the level of glutamate receptor 1 phosphorylation at Ser845, as well as induced an impairment of long term potentiation (LTP) in the hippocampus. Importantly, DHHC2 knockdown in the hippocampus impaired the LTP induced by fear conditioning, as well as fear memory. Conclusion Our results suggest that DHHC2-mediated AKAP150 palmitoylation plays a critical role in the regulation of hippocampal synaptic plasticity and fear memory.