Fear potentiated startle increases phospholipase D (PLD) expression/activity and PLD-linked metabotropic glutamate receptor mediated post-tetanic potentiation in rat amygdala

Neurobiol Learn Mem. 2016 Feb;128:65-79. doi: 10.1016/j.nlm.2015.12.009. Epub 2015 Dec 31.

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.

Keywords: Amygdala memory mechanisms; Fear potentiated startle; Neuropharmacology; Neurophysiology; Phospholipase D; Proteomic studies.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amygdala / enzymology
  • Amygdala / physiology*
  • Animals
  • Conditioning, Classical / drug effects
  • Conditioning, Classical / physiology
  • Cyclopropanes / pharmacology
  • Electric Stimulation
  • Excitatory Postsynaptic Potentials / drug effects
  • Fear / drug effects
  • Fear / physiology*
  • Fructose-Bisphosphate Aldolase / metabolism
  • Glycine / analogs & derivatives
  • Glycine / pharmacology
  • Long-Term Potentiation* / drug effects
  • Male
  • Memory, Long-Term / drug effects
  • Memory, Long-Term / physiology
  • Neural Pathways / drug effects
  • Neural Pathways / physiology
  • Phospholipase D / antagonists & inhibitors
  • Phospholipase D / metabolism
  • Phospholipase D / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Metabotropic Glutamate / agonists
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors
  • Receptors, Metabotropic Glutamate / physiology*
  • Reflex, Startle / drug effects
  • Reflex, Startle / physiology*
  • Thalamus / physiology

Substances

  • 2-(2'-carboxy-3'-phenylcyclopropyl)glycine
  • Cyclopropanes
  • Receptors, Metabotropic Glutamate
  • Phospholipase D
  • Fructose-Bisphosphate Aldolase
  • Glycine