Calcineurin Participation in Hebbian and Homeostatic Plasticity Associated With Extinction.

Salma E Reyes-García,Martha L Escobar

doi:10.3389/fncel.2021.685838

Salma E Reyes-García, Martha L Escobar

Open Access

https://doi.org/10.3389/fncel.2021.685838

Copy DOI

Abstract

In nature, animals need to adapt to constant changes in their environment. Learning and memory are cognitive capabilities that allow this to happen. Extinction, the reduction of a certain behavior or learning previously established, refers to a very particular and interesting type of learning that has been the basis of a series of therapies to diminish non-adaptive behaviors. In recent years, the exploration of the cellular and molecular mechanisms underlying this type of learning has received increasing attention. Hebbian plasticity (the activity-dependent modification of the strength or efficacy of synaptic transmission), and homeostatic plasticity (the homeostatic regulation of plasticity) constitute processes intimately associated with memory formation and maintenance. Particularly, long-term depression (LTD) has been proposed as the underlying mechanism of extinction, while the protein phosphatase calcineurin (CaN) has been widely related to both the extinction process and LTD. In this review, we focus on the available evidence that sustains CaN modulation of LTD and its association with extinction. Beyond the classic view, we also examine the interconnection among extinction, Hebbian and homeostatic plasticity, as well as emergent evidence of the participation of kinases and long-term potentiation (LTP) on extinction learning, highlighting the importance of the balance between kinases and phosphatases in the expression of extinction. Finally, we also integrate data that shows the association between extinction and less-studied phenomena, such as synaptic silencing and engram formation that open new perspectives in the field.

Highlights

Extinction from the perspective of classical conditioning can be defined as the reduction or temporal inhibition of the conditioned response (CR) that takes place once established a CS-US association and the CS is repeatedly presented in the absence of the US, while for instrumental learning, extinction represents the reduction in responses, when a response (R) that was previously followed by an appetitive outcome (O) is not followed by that outcome anymore (Myers and Davis, 2002; Myers et al, 2006; Herry et al, 2010)
It is relevant to mention that metaplasticity differential regulation by kinases/phosphatases or neurotrophic factors could play a role on extinction, e.g., our group reported that the blockade of protein kinase C (PKC) but not PKA prevented the long-term potentiation (LTP) impairment produced by conditioned taste aversion (CTA) training (Rodríguez-Durán and Escobar, 2014), revealing differential roles of protein kinases on metaplasticity
We have described experimental evidence supporting that low Ca2+ influx triggers the activation of CaN, which in turn leads to the AMPARs internalization, calmodulin-dependent kinase II (CaMKII) inactivation and CREB repression, promoting the expression of long-term depression (LTD), depotentiation and extinction

Summary

Introduction

Extinction from the perspective of classical conditioning can be defined as the reduction or temporal inhibition of the conditioned response (CR) that takes place once established a CS-US (conditioned stimulus-unconditioned stimulus) association and the CS is repeatedly presented in the absence of the US, while for instrumental learning, extinction represents the reduction in responses, when a response (R) that was previously followed by an appetitive outcome (O) is not followed by that outcome anymore (Myers and Davis, 2002; Myers et al, 2006; Herry et al, 2010).Extinction Modulation by CalcineurinThis reduction of a previously learned behavior is a natural and adaptive process that allows animals to re-learn associations about their environment. As extinction refers to a new learning, the neural basis of acquisition of conditioning (i.e., synaptic plasticity) have been associated as underlying mechanisms of extinction, as we will discuss later.

Results

Conclusion