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Corticotropin-releasing factor receptors couple to multiple g-proteins to activate diverse intracellular signaling pathways in mouse hippocampus: role in neuronal excitability and associative learning

By T. (Thomas) Blank, Ingrid Nijholt, Dimitris Grammatopoulos, Harpal S. Randeva, Edward W. Hillhouse and Joachim Spiess


Corticotropin-releasing factor (CRF) exerts a key neuroregulatory control on stress responses in various regions of the mammalian brain, including the hippocampus. Using hippocampal slices, extracts, and whole animals, we investigated the effects of human/rat CRF (h/rCRF) on hippocampal neuronal excitability and hippocampus-dependent learning in two mouse inbred strains, BALB/c and C57BL/6N. Intracellular recordings from slices revealed that application of h/rCRF increased the neuronal activity in both mouse inbred strains. Inhibition of protein kinase C (PKC) by bisindolylmaleimide I (BIS-I) prevented the h/rCRF effect only in hippocampal slices from BALB/c mice but not in slices from C57BL/6N mice. Inhibition of cAMP-dependent protein kinase (PKA) by H-89 abolished the h/rCRF effect in slices from C57BL/6N mice, with no effect in slices from BALB/c mice. Accordingly, h/rCRF elevated PKA activity in hippocampal slices from C57BL/6N mice but increased only PKC activity in the hippocampus of BALB/c mice. These differences in h/rCRF signal transduction were also observed in hippocampal membrane suspensions from both mouse strains. In BALB/c mice, hippocampal CRF receptors coupled to Gq/11 during stimulation by h/rCRF, whereas they coupled to Gs, Gq/11, and Gi in C57BL/6N mice. As expected on the basis of the slice experiments, h/rCRF improved context-dependent fear conditioning of BALB/c mice in behavioral experiments, and BIS-I prevented this effect. However, although h/rCRF increased neuronal spiking in slices from C57BL/6N mice, it did not enhance conditioned fear. These results indicate that the CRF system activates different intracellular signaling pathways in mouse hippocampus and may have distinct effects on associative learning depending on the mouse strain investigated

Topics: RC0321, QL
Publisher: Society for Neuroscience
Year: 2003
OAI identifier:

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  1. (1973). A gene influencing active avoidance performance in mice. doi
  2. (1990). A novel mechanism of action of corticotropin releasing factor in rat Leydig cells. doi
  3. (2001). A single amino acid serves as an affinity switch between the receptor and the binding protein of corticotropin-releasing factor: implications for the design of agonists and antagonists. doi
  4. (1997). A surface on the G protein betasubunitinvolvedininteractionswithadenylylcyclases.ProcNatlAcadSci USA 94:2711–2714. DobkinC,RabeA,DumasR,ElIdrissiA,HaubenstockH,BrownWT
  5. (1992). Blanketal.• CRF-MediatedExcitabilityinMouseHippocampusbinding of corticotropin-releasing factor and adenylate cyclase activity in the rat brain. Prog Neuropsychopharmacol Biol Psychiatry 16:581–586.
  6. (1988). CERsuppression,passive-avoidancelearning,andstress-induced suppression of drinking in the Syracuse high- and low-avoidance strains of rats (Rattus norvegicus). doi
  7. (1981). Characterization of a 41-residue ovinehypothalamicpeptidethatstimulatessecretionofcorticotropinand beta-endorphin. doi
  8. (1987). Characterization of corticotropin-releasing factor receptor-mediated adenylate cyclase activity in the rat central nervous system. Synapse 1:572–581. doi
  9. (1983). Corticotropin releasing factor decreases postburst hyperpolarizations and excites hippocampal neurons. doi
  10. (1985). Corticotropin-releasing factor and behavior. Fed Proc 44:259–263.
  11. (1998). Corticotropin-releasing factor produces a long-lasting enhancement of synaptic efficacy in the hippocampus. doi
  12. (2000). Corticotropin-releasing factor produces a protein synthesis-dependent long-lasting potentiation in dentate gyrus neurons.
  13. (1994). Corticotropin-releasingfactorstimulatesCa 2influxincultured rat astrocytes.
  14. (1984). Corticotropinreleasingfactor(CRF)-likeimmunoreactivity in the rat central nervous system: extrahypothalamic distribution. Peptides 5:53–69. doi
  15. (1986). Corticotropinreleasingfactorreceptor-mediatedstimulationofadenylatecyclase activity in the rat brain.
  16. (1998). Coupling of the PTH/PTHrP receptor to multiple G-proteins: direct demonstration of receptor activation of Gs, Gq/11, and Gi(1) by [alpha32P]GTP-gamma-azidoanilide photoaffinity labeling. Endocrine 8:201–209.
  17. (1998). Different training procedures recruit either one or two critical periods for contextual memory consolidation, each of which requires protein synthesis and PKA.
  18. (1992). Differential contribution of amygdala and hippocampus to contextual and cued fear conditioning. doi
  19. (2000). Distribution of mRNAs encoding CRF receptorsinbrainandpituitaryofratandmouse.JCompNeurol428:191–212.
  20. (1998). Effect of reduced myristoylated alanine-rich C kinase substrate expression on hippocampal mossy fiber development and spatial learning in mutant mice: transgenic rescue and interactions with gene background. doi
  21. (1985). Enhancement of hippocampally-mediated learning and protein kinase C activity by oxiracetam in learning-impaired DBA/2 mice. doi
  22. (1973). Freezingasanavoidanceresponse:anotherlook at the operant-respondent distinction.
  23. (1987). Genetic factors and the measurement of exploratory activity. doi
  24. (1991). Identification of receptoractivated G proteins with photoreactive GTP analog, [alpha32P]GTP azidoanilide. Methods Enzymol 195:286–301. doi
  25. (2000). Impairment of conditioned contextual fear of C57BL/6J mice by intracerebral injections of the NMDA receptor antagonist APV. doi
  26. (1994). Lesions of the dorsal hippocampal formation interfere with background but not foreground contextual fear conditioning.
  27. (1995). Link between emotional memory and anxiety states: a study by principal component analysis. doi
  28. (1985). Measurement of protein using bicinchoninic acid. doi
  29. (1992). Modality-specific retrograde amnesia of fear. doi
  30. (1999). Modulationoflearning and anxiety by corticotropin-releasing factor (CRF) and stress: differential roles of CRF receptors 1 and 2.
  31. (2001). Mouse strain differences in opiate reward learning are explained by differences in anxiety, not reward or learning.
  32. (2001). Multiple brain-memory systems: the whole does not equal the sum of its parts. doi
  33. (1979). Naloxoneandshock-elicitedfreezinginthe rat.
  34. (2001). Neurobiology of pavlovian fear conditioning. doi
  35. (1983). Organizationofovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain:animmunohistochemicalstudy.Neuroendocrinology36:165–186.
  36. (1969). Passive and active reactions to feareliciting stimuli.
  37. (1986). Phorbol esters mimic some cholinergic actions in hippocampal pyramidal neurons.
  38. (1983). PhorbolestersincreasetheamountofCa 2, phospholipid-dependent protein kinase associated with plasma membrane.
  39. (1981). Primary structure of corticotropinreleasing factor from ovine hypothalamus. doi
  40. (2002). Priming of long-term potentiation in mouse hippocampus by corticotropin-releasing factor and acute stress: implications for hippocampus-dependent learning.
  41. (2001). Protein kinase A-mediated phosphorylation of serine 357 of the mouse prostacyclin receptor regulatesitscouplingtoGs-,toGi-,andtoGq-coupledeffectorsignaling.JBiol Chem 276:33596–33607. doi
  42. (2000). ProteinkinaseAmediatesthemodulationoftheslow Ca 2-dependent K current, IsAHP, by the neuropeptides CRF, VIP, and CGRP in hippocampal pyramidal neurons.
  43. (2001). Psychogenic, neurogenic, and systemic stressor effects on plasma corticosterone and behavior: mouse strain-dependent outcomes. doi
  44. (2001). Rat cerebral cortex corticotropin-releasing hormone receptors: evidence for receptor coupling to multiple G-proteins. doi
  45. (1993). Regulation of purified type I and type II adenylylcyclases by G protein beta gamma subunits.
  46. (1999). StraindifferencesinFosexpressionfollowing airpuffstartleinspontaneouslyhypertensiveandWistarKyotorats.Neuroscience 89:965–978.
  47. (1995). Stress-induceddisturbances in Morris water-maze performance: interstrain variability.
  48. (1996). Synthesisandcharacterizationofaphotoactivatableanalogofcorticotropin-releasingfactorfor specific receptor labeling.
  49. (2000). Testing neural network models of memory with behavioral experiments.
  50. (1998). The pro-convulsant actions of corticotropin-releasing hormone in the hippocampus of infant rats. doi
  51. (1984). Themodeofinheritanceofadefectinlaminationin the hippocampus of BALB/c mice.
  52. (1997). Themousebraininstereotaxiccoordinates.
  53. (1993). Type II adenylylcyclase integrates coincident signals from Gs,G i, and Gq.

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