Type VI adenylyl cyclase negatively regulates GluN2B-mediated LTD and spatial reversal learning

• Published in: Scientific reports Vol. 6; no. 1; p. 22529
• Main Authors: Chang, Ching-Pang, Lee, Cheng-Ta, Hou, Wen-Hsien, Lin, Meng-Syuan, Lai, Hsing-Lin, Chien, Chen-Li, Chang, Chen, Cheng, Pei-Lin, Lien, Cheng-Chang, Chern, Yijuang
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 02.03.2016
• Subjects: Adenylyl Cyclases - genetics; Adenylyl Cyclases - metabolism; Anatomy; Animals; Calcium signalling; Cyclic AMP response element-binding protein; Glutamic acid receptors (ionotropic); Hippocampus; Hippocampus - enzymology; Hippocampus - metabolism; Learning; Long-term depression; Long-Term Synaptic Depression - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; N-Methyl-D-aspartic acid receptors; N-Terminus; Plasticity (neural); Receptors, N-Methyl-D-Aspartate - physiology; Reversal learning; Rodents; Spatial discrimination learning
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep22529

The calcium-sensitive type VI adenylyl cyclase (AC6) is a membrane-bound adenylyl cyclase (AC) that converts ATP to cAMP under stimulation. It is a calcium-inhibited AC and integrates negative inputs from Ca(2+) and multiple other signals to regulate the intracellular cAMP level. In the present study, we demonstrate that AC6 functions upstream of CREB and negatively controls neuronal plasticity in the hippocampus. Genetic removal of AC6 leads to cyclase-independent and N-terminus of AC6 (AC6N)-dependent elevation of CREB expression, and enhances the expression of GluN2B-containing NMDA receptors in hippocampal neurons. Consequently, GluN2B-dependent calcium signaling and excitatory postsynaptic current, long-term depression, and spatial reversal learning are enhanced in the hippocampus of AC6(-/-) mice without altering the gross anatomy of the brain. Together, our results suggest that AC6 negatively regulates neuronal plasticity by modulating the levels of CREB and GluN2B in the hippocampus.