Contextual fear response is modulated by M-type K+ channels and is associated with subtle structural changes of the axon initial segment in hippocampal GABAergic neurons

Sara Arciniegas Ruiz; Eliav Tikochinsky; Vardit Rubovitch; Chaim G Pick; Bernard Attali; Sara Arciniegas Ruiz; Eliav Tikochinsky; Vardit Rubovitch; Chaim G Pick; Bernard Attali

doi:10.3934/Neuroscience.2023003

AIMS Neuroscience

2023, Volume 10, Issue 1: 33-51. doi: 10.3934/Neuroscience.2023003

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Research article

Contextual fear response is modulated by M-type K+ channels and is associated with subtle structural changes of the axon initial segment in hippocampal GABAergic neurons

1.
Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
2.
Sagol School of Neuroscience, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
3.
Department of Anatomy and Anthropology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Received: 26 February 2023 Revised: 23 March 2023 Accepted: 27 March 2023 Published: 29 March 2023

Background
In the fear memory network, the hippocampus modulates contextual aspects of fear learning while mutual connections between the amygdala and the medial prefrontal cortex are widely involved in fear extinction. G-protein-coupled receptors (GPCRs) are involved in the regulation of fear and anxiety, so the regulation of GPCRs in fear signaling pathways can modulate the mechanisms of fear memory acquisition, consolidation and extinction. Various studies suggested a role of M-type K+ channels in modulating fear expression and extinction, although conflicting data prevented drawing of clear conclusions. In the present work, we examined the impact of M-type K+ channel blockade or activation on contextual fear acquisition and extinction. In addition, regarding the pivotal role of the hippocampus in contextual fear conditioning (CFC) and the involvement of the axon initial segment (AIS) in neuronal plasticity, we investigated whether structural alterations of the AIS in hippocampal neurons occurred during contextual fear memory acquisition and short-time extinction in mice in a behaviorally relevant context.

Results
When a single systemic injection of the M-channel blocker XE991 (2 mg/kg, IP) was carried out 15 minutes before the foot shock session, fear expression was significantly reduced. Expression of c-Fos was increased following CFC, mostly in GABAergic neurons at day 1 and day 2 post-fear training in CA1 and dentate gyrus hippocampal regions. A significantly longer AIS segment was observed in GABAergic neurons of the CA1 hippocampal region at day 2.

Conclusions
Our results underscore the role of M-type K + channels in CFC and the importance of hippocampal GABAergic neurons in fear expression.
- fear conditioning,
- GABAergic neurons,
- hippocampus,
- neuronal plasticity,
- potassium channels
Citation: Sara Arciniegas Ruiz, Eliav Tikochinsky, Vardit Rubovitch, Chaim G Pick, Bernard Attali. Contextual fear response is modulated by M-type K+ channels and is associated with subtle structural changes of the axon initial segment in hippocampal GABAergic neurons[J]. AIMS Neuroscience, 2023, 10(1): 33-51. doi: 10.3934/Neuroscience.2023003

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Abstract

Background

In the fear memory network, the hippocampus modulates contextual aspects of fear learning while mutual connections between the amygdala and the medial prefrontal cortex are widely involved in fear extinction. G-protein-coupled receptors (GPCRs) are involved in the regulation of fear and anxiety, so the regulation of GPCRs in fear signaling pathways can modulate the mechanisms of fear memory acquisition, consolidation and extinction. Various studies suggested a role of M-type K+ channels in modulating fear expression and extinction, although conflicting data prevented drawing of clear conclusions. In the present work, we examined the impact of M-type K+ channel blockade or activation on contextual fear acquisition and extinction. In addition, regarding the pivotal role of the hippocampus in contextual fear conditioning (CFC) and the involvement of the axon initial segment (AIS) in neuronal plasticity, we investigated whether structural alterations of the AIS in hippocampal neurons occurred during contextual fear memory acquisition and short-time extinction in mice in a behaviorally relevant context.

Results

When a single systemic injection of the M-channel blocker XE991 (2 mg/kg, IP) was carried out 15 minutes before the foot shock session, fear expression was significantly reduced. Expression of c-Fos was increased following CFC, mostly in GABAergic neurons at day 1 and day 2 post-fear training in CA1 and dentate gyrus hippocampal regions. A significantly longer AIS segment was observed in GABAergic neurons of the CA1 hippocampal region at day 2.

Conclusions

Our results underscore the role of M-type K + channels in CFC and the importance of hippocampal GABAergic neurons in fear expression.

Abbreviations

AIS

Axon initial segment

AnkG

Ankyrin G

BLA

Basolateral amygdala

CFC

Contextual fear conditioning

CRP

Context Re-exposure Procedure

Conditioned stimulus

Dentate gyrus of hippocampus

GPCRs

G-protein-coupled receptors

IHC

Immunohistochemistry

Infralimbic prefrontal cortex

Intraperitoneal

MAP2

Microtubule-associated protein 2

mPFC

Medial prefrontal cortex

RTG

Retigabine

Unconditioned stimulus

vGAT

Vesicular GABA transporter

vGLUT

Vesicular glutamate transporter

Acknowledgments

We would like to thank the members of the Animal Facility department for taking care of the animal maintenance and particularly to Dr. Lior Bikoveski, the core facility manager for his technical support in the behavioral equipment during our experiments. Bernard Attali holds the Andy Libach Professorial Chair in clinical pharmacology and toxicology.

Conflict of interests

The authors declare that they have no competing interests.

Funding

This work was supported by a grant from the Israel Science Foundation (ISF 1365/17) to BA.

Authors' contributions

Study concept and design: S.A.R and B.A; Performance of experiments: V.R, S.A.R. and E.T; Analysis and interpretation of data: C.G.P, S.A.R and B.A; Drafting of the manuscript: S.A.R and B.A.

Availability of data and materials

All data needed to evaluate the conclusions in the paper are present in the paper. Additional data related to this paper may be requested from the authors.

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