title: Blockade of Cav2.1-mediated NMDA receptor signaling disrupts conditioned fear extinction.
abstract: Although fear extinction requires N-methyl-d-aspartate (NMDA) receptor signaling, Cav2.1-regulated synaptic function in extinction remains unknown. This study examined whether Cav2.1-mediated signaling plays role in consolidation of extinction. Wild-type mice received intracerebroventricular injection of Cav2.1 blocker (ω-agatoxin IVA, 4.0 pg/side) showed impaired extinction behavior and increased expression of CREB-dependent gene Arc in medial prefrontal cortex (mPFC). Intra-mPFC injections of NMDA receptor antagonist (MK-801, 0.5 μg/midline), which was ineffective in wild-type controls, blocked extinction in heterozygous rolling Nagoya (rol/+) mice carrying Cav2.1α1 gene mutation rol/+ mice. These results indicate that Cav2.1-mediated NMDA receptor signaling is functional pathway in mPFC-dependent fear extinction. Our results also indicate that the combination of pharmacological and genetic approaches can be used to study functional signaling pathways in neuronal circuits.
authors.affiliation: Research Resources Center, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Kimie
authors.initials: K
authors.lastname: Niimi
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, PR China.
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Han
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Research Resources Center, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Yoshimoto
authors.affiliation: Hefei First People's Hospital, Huaihe Road 390, Hefei 230061, PR China.
authors.forename: Fu
authors.initials: F
authors.lastname: Dai
authors.affiliation: Department of Endocrinology and Metabolism, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, PR China.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Teng
authors.affiliation: Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1690, USA.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Tian
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, PR China. Electronic address: liwd@sjtu.edu.cn.
authors.forename: Weidong
authors.initials: W
authors.lastname: Li
authors.affiliation: Research Resources Center, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, PR China. Electronic address: etakahashi@brain.riken.jp.
authors.forename: Eiki
authors.initials: E
authors.lastname: Takahashi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000378:metabolism*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005108:Extinction, Psychological / Q000187:drug effects; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D020867:omega-Agatoxin IVA / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D016291:Dizocilpine Maleate; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D020867:omega-Agatoxin IVA
keywords: Cav2.1; Fear extinction; Neuronal circuits; Rolling Nagoya mice; ω-Agatoxin IVA