title: Decreased anxiety-like behavior and Gαq/11-dependent responses in the amygdala of mice lacking TRPC4 channels.
abstract: Transient receptor potential (TRP) channels are abundant in the brain where they regulate transmission of sensory signals. The expression patterns of different TRPC subunits (TRPC1, 4, and 5) are consistent with their potential role in fear-related behaviors. Accordingly, we found recently that mutant mice lacking a specific TRP channel subunit, TRPC5, exhibited decreased innate fear responses. Both TRPC5 and another member of the same subfamily, TRPC4, form heteromeric complexes with the TRPC1 subunit (TRPC1/5 and TRPC1/4, respectively). As TRP channels with specific subunit compositions may have different functional properties, we hypothesized that fear-related behaviors could be differentially controlled by TRPCs with distinct subunit arrangements. In this study, we focused on the analysis of mutant mice lacking the TRPC4 subunit, which, as we confirmed in experiments on control mice, is expressed in brain areas implicated in the control of fear and anxiety. In behavioral experiments, we found that constitutive ablation of TRPC4 was associated with diminished anxiety levels (innate fear). Furthermore, knockdown of TRPC4 protein in the lateral amygdala via lentiviral-mediated gene delivery of RNAi mimicked the behavioral phenotype of constitutive TRPC4-null (TRPC4(-/-)) mouse. Recordings in brain slices demonstrated that these behavioral modifications could stem from the lack of TRPC4 potentiation in neurons in the lateral nucleus of the amygdala through two Gαq/11 protein-coupled signaling pathways, activated via Group I metabotropic glutamate receptors and cholecystokinin 2 receptors, respectively. Thus, TRPC4 and the structurally and functionally related subunit, TRPC5, may both contribute to the mechanisms underlying regulation of innate fear responses.
authors.affiliation: Howard Hughes Medical Institute, Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts 02115, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02478, and Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg 194223, Russia.
authors.forename: Antonio
authors.initials: A
authors.lastname: Riccio
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Evgeny
authors.initials: E
authors.lastname: Tsvetkov
authors.forename: Svetlana
authors.initials: S
authors.lastname: Gapon
authors.forename: Gui Lan
authors.initials: GL
authors.lastname: Yao
authors.forename: Kiersten S
authors.initials: KS
authors.lastname: Smith
authors.forename: Elif
authors.initials: E
authors.lastname: Engin
authors.forename: Uwe
authors.initials: U
authors.lastname: Rudolph
authors.forename: Vadim Y
authors.initials: VY
authors.lastname: Bolshakov
authors.forename: David E
authors.initials: DE
authors.lastname: Clapham
mesh_terms: D000679:Amygdala / Q000378:metabolism*; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D015536:Down-Regulation / Q000235:genetics; D005073:Evoked Potentials, Somatosensory / Q000235:genetics; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050052:TRPC Cation Channels / Q000096:biosynthesis / Q000172:deficiency*
chemical_list: D050052:TRPC Cation Channels; C489571:TRPC4 ion channel; D043802:GTP-Binding Protein alpha Subunits, Gq-G11
keywords: TRP channel; TRPC4; amygdala; anxiety; cholecystokinin 4; fear