title: 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.
abstract: 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 G(q/11) during stimulation by h/rCRF, whereas they coupled to G(s), G(q/11), and G(i) 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.
authors.affiliation: Department of Molecular Neuroendocrinology, Max Planck Institute for Experimental Medicine, D-37075 Goettingen, Germany. blank@em.mpg.de
authors.forename: Thomas
authors.initials: T
authors.lastname: Blank
authors.forename: Ingrid
authors.initials: I
authors.lastname: Nijholt
authors.forename: Dimitris K
authors.initials: DK
authors.lastname: Grammatopoulos
authors.forename: Harpal S
authors.initials: HS
authors.lastname: Randeva
authors.forename: Edward W
authors.initials: EW
authors.lastname: Hillhouse
authors.forename: Joachim
authors.initials: J
authors.lastname: Spiess
mesh_terms: D000818:Animals; D001245:Association Learning / Q000187:drug effects / Q000502:physiology*; D003214:Conditioning, Classical; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005239:Fear / Q000502:physiology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007424:Intracellular Fluid / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism*; D015290:Second Messenger Systems / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013045:Species Specificity
chemical_list: D004791:Enzyme Inhibitors; D018019:Receptors, Corticotropin-Releasing Hormone; D003346:Corticotropin-Releasing Hormone; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D019204:GTP-Binding Proteins