title: A presynaptic role for PKA in synaptic tagging and memory.
abstract: Protein kinase A (PKA) and other signaling molecules are spatially restricted within neurons by A-kinase anchoring proteins (AKAPs). Although studies on compartmentalized PKA signaling have focused on postsynaptic mechanisms, presynaptically anchored PKA may contribute to synaptic plasticity and memory because PKA also regulates presynaptic transmitter release. Here, we examine this issue using genetic and pharmacological application of Ht31, a PKA anchoring disrupting peptide. At the hippocampal Schaffer collateral CA3-CA1 synapse, Ht31 treatment elicits a rapid decay of synaptic responses to repetitive stimuli, indicating a fast depletion of the readily releasable pool of synaptic vesicles. The interaction between PKA and proteins involved in producing this pool of synaptic vesicles is supported by biochemical assays showing that synaptic vesicle protein 2 (SV2), Rim1, and SNAP25 are components of a complex that interacts with cAMP. Moreover, acute treatment with Ht31 reduces the levels of SV2. Finally, experiments with transgenic mouse lines, which express Ht31 in excitatory neurons at the Schaffer collateral CA3-CA1 synapse, highlight a requirement for presynaptically anchored PKA in pathway-specific synaptic tagging and long-term contextual fear memory. These results suggest that a presynaptically compartmentalized PKA is critical for synaptic plasticity and memory by regulating the readily releasable pool of synaptic vesicles.
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, PA 19104-6018, USA.
authors.forename: Alan Jung
authors.initials: AJ
authors.lastname: Park
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, PA 19104-6018, USA.
authors.forename: Robbert
authors.initials: R
authors.lastname: Havekes
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, PA 19104-6018, USA.
authors.forename: Jennifer Hk
authors.initials: JH
authors.lastname: Choi
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, PA 19104-6018, USA.
authors.forename: Vince
authors.initials: V
authors.lastname: Luczak
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, PA 19104-6018, USA.|Department of Pediatrics, Emory University, VAMC, 1670 Clairmont Rd Atlanta, GA 30033, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Nie
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, PA 19104-6018, USA.
authors.forename: Ted
authors.initials: T
authors.lastname: Huang
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, PA 19104-6018, USA.
authors.forename: Ted
authors.initials: T
authors.lastname: Abel
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005239:Fear / Q000502:physiology; D019204:GTP-Binding Proteins / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D011506:Proteins / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism
chemical_list: D054758:A Kinase Anchor Proteins; C400224:Ht 31 protein, synthetic; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D011506:Proteins; C491490:Rims1 protein, mouse; C494209:Snap25 protein, mouse; C489614:Sv2a protein, mouse; D050825:Synaptosomal-Associated Protein 25; D017868:Cyclic AMP-Dependent Protein Kinases; D019204:GTP-Binding Proteins
keywords: Ht31; PKA; PKA anchoring; SV2; Synaptic tagging