title: Fear potentiated startle increases phospholipase D (PLD) expression/activity and PLD-linked metabotropic glutamate receptor mediated post-tetanic potentiation in rat amygdala.
abstract: Long-term memory (LTM) of fear stores activity dependent modifications that include changes in amygdala signaling. Previously, we identified an enhanced probability of release of glutamate mediated signaling to be important in rat fear potentiated startle (FPS), a well-established translational behavioral measure of fear. Here, we investigated short- and long-term synaptic plasticity in FPS involving metabotropic glutamate receptors (mGluRs) and associated downstream proteomic changes in the thalamic-lateral amygdala pathway (Th-LA). Aldolase A, an inhibitor of phospholipase D (PLD), expression was reduced, concurrent with significantly elevated PLD protein expression. Blocking the PLD-mGluR signaling significantly reduced PLD activity. While transmitter release probability increased in FPS, PLD-mGluR agonist and antagonist actions were occluded. In the unpaired group (UNP), blocking the PLD-mGluR increased while activating the receptor decreased transmitter release probability, consistent with decreased synaptic potentials during tetanic stimulation. FPS Post-tetanic potentiation (PTP) immediately following long-term potentiation (LTP) induction was significantly increased. Blocking PLD-mGluR signaling prevented PTP and reduced cumulative PTP probability but not LTP maintenance in both groups. These effects are similar to those mediated through mGluR7, which is co-immunoprecipitated with PLD in FPS. Lastly, blocking mGluR-PLD in the rat amygdala was sufficient to prevent behavioral expression of fear memory. Thus, our study in the Th-LA pathway provides the first evidence for PLD as an important target of mGluR signaling in amygdala fear-associated memory. Importantly, the PLD-mGluR provides a novel therapeutic target for treating maladaptive fear memories in posttraumatic stress and anxiety disorders.
authors.affiliation: Department of Pharmacology & Toxicology, University of Texas Medical Branch, Galveston, TX, United States; UTMB Mitchell Center for Neurodegenerative Diseases, Department of Neurology, University of Texas Medical Branch, Galveston, TX, United States. Electronic address: bakrishn@utmb.edu.
authors.forename: Balaji
authors.initials: B
authors.lastname: Krishnan
authors.affiliation: Department of Pharmacology & Toxicology, University of Texas Medical Branch, Galveston, TX, United States.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Scott
authors.affiliation: Department of Pharmacology & Toxicology, University of Texas Medical Branch, Galveston, TX, United States.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Pollandt
authors.affiliation: Department of Pharmacology & Toxicology, University of Texas Medical Branch, Galveston, TX, United States.
authors.forename: Bradley
authors.initials: B
authors.lastname: Schroeder
authors.affiliation: UTMB NHLBI Proteomics Center, Department of Biochemistry & Molecular Biology, University of Texas Medical Branch, Galveston, TX, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kurosky
authors.affiliation: Department of Pharmacology & Toxicology, University of Texas Medical Branch, Galveston, TX, United States.
authors.forename: Patricia
authors.initials: P
authors.lastname: Shinnick-Gallagher
mesh_terms: D000679:Amygdala / Q000201:enzymology / Q000502:physiology*; D000818:Animals; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology; D003521:Cyclopropanes / Q000494:pharmacology; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D005634:Fructose-Bisphosphate Aldolase / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D057567:Memory, Long-Term / Q000187:drug effects / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D010739:Phospholipase D / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology*; D013788:Thalamus / Q000502:physiology
chemical_list: C099854:2-(2'-carboxy-3'-phenylcyclopropyl)glycine; D003521:Cyclopropanes; D018094:Receptors, Metabotropic Glutamate; D010739:Phospholipase D; D005634:Fructose-Bisphosphate Aldolase; D005998:Glycine
keywords: Amygdala memory mechanisms; Fear potentiated startle; Neuropharmacology; Neurophysiology; Phospholipase D; Proteomic studies