title: Gastrin-releasing peptide signaling plays a limited and subtle role in amygdala physiology and aversive memory.
abstract: Links between synaptic plasticity in the lateral amygdala (LA) and Pavlovian fear learning are well established. Neuropeptides including gastrin-releasing peptide (GRP) can modulate LA function. GRP increases inhibition in the LA and mice lacking the GRP receptor (GRPR KO) show more pronounced and persistent fear after single-trial associative learning. Here, we confirmed these initial findings and examined whether they extrapolate to more aspects of amygdala physiology and to other forms of aversive associative learning. GRP application in brain slices from wildtype but not GRPR KO mice increased spontaneous inhibitory activity in LA pyramidal neurons. In amygdala slices from GRPR KO mice, GRP did not increase inhibitory activity. In comparison to wildtype, short- but not long-term plasticity was increased in the cortico-lateral amygdala (LA) pathway of GRPR KO amygdala slices, whereas no changes were detected in the thalamo-LA pathway. In addition, GRPR KO mice showed enhanced fear evoked by single-trial conditioning and reduced spontaneous firing of neurons in the central nucleus of the amygdala (CeA). Altogether, these results are consistent with a potentially important modulatory role of GRP/GRPR signaling in the amygdala. However, administration of GRP or the GRPR antagonist (D-Phe(6), Leu-NHEt(13), des-Met(14))-Bombesin (6-14) did not affect amygdala LTP in brain slices, nor did they affect the expression of conditioned fear following intra-amygdala administration. GRPR KO mice also failed to show differences in fear expression and extinction after multiple-trial fear conditioning, and there were no differences in conditioned taste aversion or gustatory neophobia. Collectively, our data indicate that GRP/GRPR signaling modulates amygdala physiology in a paradigm-specific fashion that likely is insufficient to generate therapeutic effects across amygdala-dependent disorders.
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis AG, Basel, Switzerland.
authors.forename: Frederique
authors.initials: F
authors.lastname: Chaperon
authors.forename: Markus
authors.initials: M
authors.lastname: Fendt
authors.forename: Peter H
authors.initials: PH
authors.lastname: Kelly
authors.forename: Kurt
authors.initials: K
authors.lastname: Lingenhoehl
authors.forename: Johannes
authors.initials: J
authors.lastname: Mosbacher
authors.forename: Hans-Rudolf
authors.initials: HR
authors.lastname: Olpe
authors.forename: Peter
authors.initials: P
authors.lastname: Schmid
authors.forename: Christine
authors.initials: C
authors.lastname: Sturchler
authors.forename: Kevin H
authors.initials: KH
authors.lastname: McAllister
authors.forename: P Herman
authors.initials: PH
authors.lastname: van der Putten
authors.forename: Christine E
authors.initials: CE
authors.lastname: Gee
mesh_terms: D000679:Amygdala / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D003214:Conditioning, Classical / Q000502:physiology; D005239:Fear / Q000502:physiology*; D019886:Gastrin-Releasing Peptide / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D010446:Peptide Fragments / Q000737:chemistry; D017966:Pyramidal Cells / Q000378:metabolism / Q000502:physiology; D018004:Receptors, Bombesin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D010446:Peptide Fragments; D018004:Receptors, Bombesin; C574083:bombesin (6-14), Phe(6)-Leu(NHEt)(13)-desMet(14)-; D019886:Gastrin-Releasing Peptide; D001839:Bombesin