Presynaptic Anchoring of PKA by AKAP7 is Required for Pattern Separation by Dentate Gyrus

Thesis (Ph.D.)--University of Washington, 2016-06

The intracellular signaling molecule, 3',5'-cyclic adenosine monophosphate (cAMP), is produced by a cell in response to a physiological signal. A derivative of adenosine triphosphate (ATP), cAMP is produced by adenylate cyclases (ACs) localized either to the plasma membrane (insoluble) or cytosol (soluble) and degraded by phosphodiesterases (PDEs) into adenosine monophosphate (AMP) and a phosphate group. Between its production and degradation, cAMP directly activates protein kinase A (PKA), cyclic nucleotide-gated ion channels, and exchange protein directly activated by cAMP (Epac). The activation of PKA is the dominant result of cAMP production. Since the discovery of PKA nearly fifty years ago, phosphorylation provided by PKA has been found to affect protein activity, interaction, localization, and conformation. These PKA mediated events have larger demonstrated roles in cell metabolism, migration, morphology, division, differentiation, activation, transcription and translation. Further, when PKA signaling is impaired, host behavior and health may be affected. The anchoring of PKA and other signaling and structural proteins by A-Kinase anchoring proteins (AKAPs) coordinates precise subcellular and temporally regulated activities while also sequestering aberrant PKA activity. In the hippocampus, enhanced plasticity between different neuronal populations, or long term potentiation (LTP), is considered the physiological manifestation of memory. The dentate gyrus (DG) receives cortical input from the entorhinal cortex and sends mossy fiber (MF) projections to the CA3 region of the hippocampus. The DG is thought to be responsible for processing and encoding distinct contextual associations in response to highly similar events/experiences, allowing behavioral discrimination. However, the cellular processes underlying this form of learning, known as pattern separation, are poorly understood. Here we demonstrate an essential role for presynaptic AKAP7 in anchoring PKA-RIIβ in MF axons and terminals. Mice with a DG-specific ablation of AKAP7 are selectively deficient in pattern separation but exhibit normal contextual learning and memory, suggesting a link between DG-dependent behaviors and the presynaptic anchoring of PKA by AKAP7. Moreover, genetic ablation of AKAP7 results in a loss of presynaptic and cAMP/PKA-dependent MF-CA3 long-term potentiation directly initiated by adenylyl cyclase activation without affecting tetanus-induced LTP in this pathway.