Characterization of the type VI adenylyl cyclase in the hippocampus

• Main Authors: Ching-Pang Chang, 張敬邦
• Other Authors: Yijuang Chern
• Format: Others
• Language: en_US
• Published: 2016
• Online Access: http://ndltd.ncl.edu.tw/handle/80616339303858889153

博士 === 國立陽明大學 === 生化暨分子生物研究所 === 104 === The calcium-sensitive type VI adenylyl cyclase (AC6) is a membrane-bound adenylyl cyclase (mAC) that converts ATP to cAMP under stimulation. Unlike other ACs, AC6 is of particular interest in the brain as it is expressed in neuronal cells and distributed in various brain regions (including the hippocampus). Furthermore, it is a calcium-inhibited AC and integrates negative inputs from Ca2+ and multiple other signals (such as Gαi, PKA, PKC, and NO) to regulate the intracellular cAMP level. In addition to the production of cAMP, our group previously showed that the N-terminus of AC6 modulates neurite outgrowth by interacting with Snapin in primary hippocampal neurons and Neuro2A cells, which revealed that AC6 is an important modulator of neuritogenesis. Nonetheless, the exact function of AC6 in the brain remains largely unknown. The major goal of the present study is to understand the physiological role of AC6, an important coincident detector, in controlling brain activity. Here I demonstrate that AC6 negatively modulates the hippocampus-dependent spatial learning via controlling the levels of activated CREB and GluN2B in the hippocampus. Furthermore, I used in vitro (primary neuron culture, Ca2+ imaging, cAMP/FRET imaging, and electrophysiology recording) and in vivo (Morris water maze and fear conditioning test) approaches to demonstrate that genetic removal of AC6 led to 1) a cyclase-independent and AC6N-dependent elevation of CREB activity, 2) elevated spine density and intrinsic excitability (including increased membrane time constant, lower rheobase, reduced action potential threshold), 3) enhanced expression of the GluN2B-containing NMDA receptors, 4) higher GluN2B-mediated functions (including calcium influx, cAMP elevation, excitatory postsynaptic current, and LTD) in the hippocampus, and 5) better hippocampus-dependent spatial reversal learning. Together, these results reveal a new function of AC6 in the hippocampus that is independent of cAMP production in the modulation of CREB, GluN2B, and memory flexibility. Given that enhanced expression of GluN2B might prevent memory decline during neurodegenerative diseases, AC6 potentially may serve as a new drug target for the development of therapeutic interventions for neurodegenerative diseases.