Calcineurin Participation in Hebbian and Homeostatic Plasticity Associated With Extinction

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.

Chronic facial inflammatory pain-induced anxiety is associated with bilateral deactivation of the rostral anterior cingulate cortex

“…2008;Li et al, 2010;Koga et al, 2015;Shen et al, 2015;Chen et al, 2016). Thus chronic pain-and activity-dependent changes in excitatory synaptic transmission appear to be similar (for review see Josselyn and Tonegawa, 2020;Reyes-García and Escobar, 2021). This raises the possibility that recovery from inflammatory pain is an extinction-like process.…”

“…This raises the possibility that recovery from inflammatory pain is an extinction-like process. One theory of memory extinction is engram silencing as extinction protocols also produce depotentiation; that is, the reversal of LTP (for review see Josselyn and Tonegawa, 2020;Reyes-García and Escobar, 2021). According to this theory, recovery from inflammatory pain would thus be a simple return of potentiated ACC excitatory synaptic transmission to baseline levels.…”

Assessing Changes in Synaptic Plasticity Using an Awake Closed-Head Injury Model of Mild Traumatic Brain Injury

“…It was originally proposed to be a mechanism of forgetting (30). The induction of LTD usually involves group I mGluRs, which lead to the activation of phosphatases such as calcineurin (31). Phosphatases and kinases are common cellular switches, where kinases add a phosphate group, while phosphatases remove the phosphate group (32).…”

Molecular Mechanisms Underlying NMDARs Dysfunction and Their Role in ADHD Pathogenesis

“…CREB is a transcription factor that regulates expression of numerous neuropeptides and is considered one of the most important factors involved in neuroplasticity and long-term memory formation. Conversely, in LTD, low calcium influx activates serine/threonine-protein phosphatase 2B (PP2B, also known as calcineurin), which dephosphorylates both CREB and the AMPAR GluA1 subunit [52,53]. Consequently, (B) The binding of glycine (Gly) to the GluN1 subunit and glutamate (Glu) to the GluN2 subunit triggers the closure of the ABD clam-shell around the agonists.…”