title: Regulation of neuronal plasticity and fear by a dynamic change in PAR1-G protein coupling in the amygdala.
abstract: Fear memories are acquired through neuronal plasticity, an orchestrated sequence of events regulated at circuit and cellular levels. The conventional model of fear acquisition assumes unimodal (for example, excitatory or inhibitory) roles of modulatory receptors in controlling neuronal activity and learning. Contrary to this view, we show that protease-activated receptor-1 (PAR1) promotes contrasting neuronal responses depending on the emotional status of an animal by a dynamic shift between distinct G protein-coupling partners. In the basolateral amygdala of fear-naive mice PAR1 couples to Gαq/11 and Gαo proteins, while after fear conditioning coupling to Gαo increases. Concurrently, stimulation of PAR1 before conditioning enhanced, but afterwards it inhibited firing of basal amygdala neurons. An initial impairment of the long-term potentiation (LTP) in PAR1-deficient mice was transformed into an increase in LTP and enhancement of fear after conditioning. These effects correlated with more frequent 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid (AMPA) receptor-mediated miniature post synaptic events and increased neuronal excitability. Our findings point to experience-specific shifts in PAR1-G protein coupling in the amygdala as a novel mechanism regulating neuronal excitability and fear.
authors.affiliation: Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, UK.
authors.forename: J-M
authors.initials: JM
authors.lastname: Bourgognon
authors.forename: E
authors.initials: E
authors.lastname: Schiavon
authors.forename: H
authors.initials: H
authors.lastname: Salah-Uddin
authors.forename: A E
authors.initials: AE
authors.lastname: Skrzypiec
authors.forename: B K
authors.initials: BK
authors.lastname: Attwood
authors.forename: R S
authors.initials: RS
authors.lastname: Shah
authors.forename: S G
authors.initials: SG
authors.lastname: Patel
authors.forename: M
authors.initials: M
authors.lastname: Mucha
authors.forename: R A
authors.initials: RA
authors.lastname: John Challiss
authors.forename: I D
authors.initials: ID
authors.lastname: Forsythe
authors.forename: R
authors.initials: R
authors.lastname: Pawlak
mesh_terms: D000679:Amygdala / Q000737:chemistry / Q000502:physiology*; D000818:Animals; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects / Q000502:physiology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000502:physiology; D017288:Pain Threshold; D018408:Patch-Clamp Techniques; D011758:Pyrroles / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D044463:Receptor, PAR-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D010975:Platelet Aggregation Inhibitors
chemical_list: C415424:N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine; D009419:Nerve Tissue Proteins; D011758:Pyrroles; D011799:Quinazolines; D044463:Receptor, PAR-1; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D010975:Platelet Aggregation Inhibitors