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Updated: May 6, 2026
Trace Fear Conditioning in Mice
Published on: March 20, 2014
Blockade of Cav2.1-mediated NMDA receptor signaling disrupts conditioned fear extinction
Kimie Niimi1, Yanfei Han2, Ying Zhou2
1Research Resources Center, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
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.
Insights
This study reveals that Cav2.1 calcium channels are crucial for fear extinction memory consolidation in the medial prefrontal cortex (mPFC). Blocking these channels impairs extinction, highlighting their role in this learning process.
Area of Science:
- Neuroscience
- Molecular Biology
- Behavioral Science
Background:
- Fear extinction is a crucial learning process for adapting to changing environments.
- N-methyl-d-aspartate (NMDA) receptor signaling is essential for fear extinction.
- The specific role of Cav2.1 calcium channels in fear extinction consolidation is not well understood.
Purpose of the Study:
- To investigate the role of Cav2.1-mediated signaling in the consolidation of fear extinction.
- To determine if Cav2.1 channels are a functional component of the NMDA receptor signaling pathway in fear extinction.
Main Methods:
- Wild-type mice received intracerebroventricular injections of a Cav2.1 blocker (ω-agatoxin IVA).
- Medial prefrontal cortex (mPFC) injections of an NMDA receptor antagonist (MK-801) were administered to wild-type and Cav2.1 mutant mice (rol/+).
- Fear extinction behavior and CREB-dependent gene Arc expression in the mPFC were assessed.
Main Results:
- Cav2.1 channel blockade in wild-type mice impaired fear extinction behavior and increased Arc expression in the mPFC.
- NMDA receptor antagonist administration blocked extinction in Cav2.1 mutant mice but not in wild-type controls.
- These findings demonstrate a functional link between Cav2.1 and NMDA receptor signaling in fear extinction.
Conclusions:
- Cav2.1-mediated NMDA receptor signaling is a critical pathway in the mPFC for fear extinction consolidation.
- Combined pharmacological and genetic approaches are effective for elucidating functional signaling pathways in neuronal circuits.
- This research provides insights into the molecular mechanisms underlying fear memory regulation.
