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A Dissertation Entitled Pituitary Adenylate Cyclase Activating A Dissertation entitled Pituitary Adenylate Cyclase Activating Polypeptide and Synaptic Plasticity at Autonomic Cholinergic Synapses By Eric R. Starr Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Biomedical Sciences __________________________________________ Joseph F. Margiotta, PhD, Committee Chair __________________________________________ David R. Giovanucci, PhD, Committee Member __________________________________________ Scott Molitor, PhD, Committee Member __________________________________________ Joshua Park, PhD, Committee Member __________________________________________ Ruili Xie, PhD, Committee Member __________________________________________ Amanda Byrant-Friedrich, Dr. rer. Nat., Dean College of Graduate Studies The University of Toledo August 2017 i Copyright 2017, Eric R. Starr This document is copyright material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. ii An Abstract of Pituitary Adenylate Cyclase Activating Polypeptide and Synaptic Plasticity at Autonomic Cholinergic Synapses By Eric R. Starr Submitted to the Graduate Faculty as partial fulfillment of the requirements of the Doctor of Philosophy Degree in Biomedical Sciences The University of Toledo July 2017 Pituitary adenylate cyclase activating polypeptide (PACAP) is a secretin family neuropeptide, localized to presynaptic terminals throughout the nervous system. In autonomic ciliary ganglion (CG) neurons, PACAP exposure engages a PACAP type 1 receptor (PAC1R) signaling cascade that rapidly enhances the function of nicotinic acetylcholine receptors (nAChR)-mediated synapses both immediately and 24, 48 and 72 hours after PACAP treatment. In this dissertation, I sought to examine the mechanisms underlying the short-term (ST) and long-term (LT) PACAP-induced synaptic plasticity in CG neurons. Our lab previously demonstrated that the immediate, ST PACAP-induced synaptic plasticity, characterized by increases in sEPSC frequency and sEPSC amplitude is dependent upon canonical AC, cAMP, PKA signaling and neuronal nitric oxide synthase (NOS1). I participated in collaborative studies to determine how PACAP stimulates nitric oxide (NO) production and elucidate the mechanisms underlying the ST PACAP-induced synaptic plasticity. Live-cell imaging revealed that PACAP stimulated NO production, an effect that required NOS1, PKA, Ca2+ influx, and nAChR activation. iii Scavenging of extracellular NO blocked the PACAP-induced synaptic plasticity supporting a role for NO retrograde signaling (post- to presynaptic) on presynaptic ACh release. Both α3*- and α7 nAChRs are potentiated by PKA phosphorylation and were required for both PACAP-induced NO synthesis and increases in sEPSC frequency and sEPSC amplitude. Coimmunoprecipitation experiments show that NOS1 associated with α7 nAChRs and α3*-nAChRs, suggesting that NOS1-nAChR physical associations could facilitate NO production to enhance ACh release from juxtaposed presynaptic terminals. The ST PACAP-induced synaptic plasticity was dependent upon localized PKA signaling by PKA anchoring proteins (AKAP). PKA regulatory-subunit overlay assays identified five AKAPs in CG lysates and inhibiting binding of the PKA regulatory subunit to AKAP blocked the ST PACAP-induced synaptic plasticity. Taken together, our findings indicate that PACAP/PAC1R signaling coordinates nAChRs, NOS1, and AKAP activities to induce targeted, retrograde plasticity at autonomic synapses. PACAP treatment also induces a LT synaptic plasticity 48 hours after PACAP washout that exhibits a similar increase in sEPSC frequency, but featured more robust increases in sEPSC amplitude. Pharmacological studies verified that PAC1R mediated AC and PLC signaling cascades was required. However, inhibition of NOS1, PKA and nAChR activiation, three critical effectors underlying the ST PACAP-induced synaptic plasticity had no effect on the LT PACAP-induced synaptic plasticity. Instead inhibition of gene transcription attenuated the LT PACAP-induced synaptic plasticity but had no effect on ST PACAP treatment. In concert with increases in sEPSC frequency and amplitude, the synaptic correlates underlying this LT PACAP-induced plasticity reflect increases in post- and presynaptic strength. The LT PACAP-induced plasticity was iv accompanied by significant increases in miniature EPSC amplitude (postsynaptic quantal size), α3*-nAChR sensitivity, mEPSC frequency and ACh release (presynaptic quantal content). No detectable differences were observed in excitability suggesting that the physiological hallmarks underlying the LT PACAP-induced plasticity are confined to presynaptic terminals and postsynaptic densities. Analysis of confocal images confirmed these findings, identify that the LT effects of PACAP significantly enhanced the size of individual presynaptic puncta and postsynaptic nAChR clusters labeled with SV2 and nAChR specific antibodies, respectively, as well as the size, density, and number of colocalized pre- and postsynaptic puncta. These results indicate that PACAP induces LT synaptic plasticity via PAC1R induced activation of AC and PLC signaling and gene transcription, an effect results in the structural rearrangement of associated pre- and postsynaptic components. Taken together, our results demonstrate that PACAP induces ST and LT plasticity through distinguishable biochemical, physiological and synaptic mechanisms. v Acknowledgments This dissertation would not have been possible had it not been for the guidance and mentoring I received from Dr. Joseph Margiotta. Dr. Margiotta’s excellent guidance and training, as well as his passion for scientific inquiry and drive for scientific discovery have and will always shape my future endeavors. I would also like to thank Samantha McKee whose support, friendship, and insights have been indispensable in the completion of this dissertation. Also, this dissertation would not have been possible had it not been for the absolute dedication, encouragement, and love I receive from my fiancé Alison as well as my family. I am so thankful for their continuous optimism, sacrifice, and support during my time at the University of Toledo. Their guidance has always inspired me to never give up and to always keep learning and reach for the stars. As dad always says: “Stay calm; Stay cool; Don’t drool in school.” vi Contents Abstract iii Acknowledgments vi Contents vii List of Tables xii List of Figures xiii List of Abbreviations xv 1 Introduction to Pituitary Adenylate Cyclase Activating Polypeptide 1 1.1 Synaptic Plasticity and Pituitary Adenylate Cyclase Activating Peptide………………………………………………………………….. 1 1.2 Synthesis and Transport of PACAP in the Nervous System………….... 3 1.3 PACAP Receptors……………………………………………………… 5 1.4 Termination of PACAP Signaling……………………………………… 9 1.5 Is PACAP a Neurotransmitter, Neuromodulator, or Both?..................... 12 1.6 PACAP Signaling at Central Synapses………………………………... 14 1.6.1 Hypothalamus…………………………………………………. 14 1.6.2 Hippocampus………………………………………………….. 16 1.6.3 Amygdala……………………………………………………... 23 vii 1.7 PACAP Signaling at Autonomic Synapses…………………………… 26 1.7.1 Ciliary Ganglion………………………………………………. 26 1.7.2 Cardiac Ganglion……………………………………………… 30 1.7.3 Submandibular Ganglion……………………………………… 31 1.7.4 Superior Cervical Ganglion…………………………………… 33 1.8 Conclusions and Dissertation Hypothesis…………………………….. 35 2 PACAP Induces Plasticity at Autonomic Synapses by nAChR- Dependent NOS1 Activation and AKAP-Mediated PKA Targeting 39 2.1 Abstract……………………………………………………………….. 39 2.2 Introduction…………………………………………………………… 41 2.3 Methods……………………………………………………………….. 43 2.3.1 Neuronal Preparation…………………………………………. 43 2.3.2 Electrophysiological Recording………………………………. 44 2.3.3 Nitric Oxide Imaging………………………………………….. 45 2.3.4 Detection of Endogenous NOS1………………………………. 47 2.3.5 nAChR-NOS1 Co-Precipitation……………………………….. 48 2.3.6 AKAP5 Detection……………………………………………… 50 2.3.7 Statistics……………………………………………………….. 51 2.4 Results…………………………………………………………………. 51 2.4.1 PACAP Stimulates NOS1 to Increase NO Levels…………….. 51 2.4.2 NO is a Retrograde Messenger………………………………… 54 2.4.3 PACAP-Induced PKA Dependent Up-regulation of α7- nAChRs Underlies NO Elevation…………………………........ 56 viii 2.4.4 Concomitant nAChR Activation Underlies PACAP/PAC1R- Induced Synaptic Plasticity……………………………………………. 61 2.4.5 nAChRs Associate with NOS1……………………………….. 66 2.4.6 AKAP5 is Present in CG Neurons and Targets PACAP/ PAC1R Signals to Synapses…………………………………… 68 2.5 Discussion……………………………………………………………... 72 3 PACAP Induces Long-term Synaptic Plasticity Through Coordinated AC and PLC Signaling and Gene Transcription 81 3.1 Introduction……………………………………………………………. 81 3.2 Methods………………………………………………………………... 83 3.2.1 Neuronal Cultures……………………………………………… 83 3.2.2 Electrophysiology……………………………………………… 84 3.2.3 Drug Treatments……………………………………………….. 85 3.2.4 Statistical Evaluation…………………………………………... 86 3.3 Results…………………………………………………………………. 87 3.3.1 PACAP Induces Short-term and Long-term Synaptic Plasticity……………………………………………………….. 87 3.3.2 PACAP Induces Long-term Synaptic Plasticity via Adenylate Cyclase/cAMP and Phospholipase C-Mediated Signal Transduction............................................................................... 90 3.3.3 The ST and LT PACAP-Induced Synaptic Plasticity are Mechanistically Distinct………………………………………. 92 ix 3.3.4 The LT PACAP-Induced Synaptic Plasticity Requires Gene Transcription but is Independent of PAC1R Internalization…... 97 3.4 Discussion………………………………………………………………
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