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.

Keywords: Hebbian and homeostatic plasticity; calcineurin; depotentiation; extinction; kinases and phosphatases; long-term depression.

FIGURE 1

LTD, depotentiation and metaplasticity graphic representation. (A) Graphic representation of LTD (green circles) and depotentiation (blue circles). Blue arrows indicate application of low frequency stimulation in order to induce LTD or depotentiation. (B) Metaplasticity. After receiving a weak stimulation (green arrow heads), LTP cannot be induced by applying a high frequency stimulation (green arrows) capable of inducing this phenomenon in a control preparation as observed in the inset. That is, the previous stimulation modifies the threshold to induce LTP.

FIGURE 2

Calcineurin structure. (A) Inactivated CaN. Representation of CaN-A catalytic subunit (blue) and the regulatory subunit CaN-B (green). CaN-A consists of a catalytic cavity, a CaN-B binding domain, a calmodulin binding domain (CaM-BD) and an autoinhibitory domain (AID). CaN-B possesses four binding sites for Ca²⁺, two of high affinity typically occupied by Ca²⁺ at basal levels. The AID occupies the catalytic cavity when CaN is inactive. (B) Activated CaN. At low Ca²⁺ influx, Ca²⁺ binds to the low affinity sites at CaN-B and the Ca²⁺/CaM complex binds to CaM-BD allowing AID removal from the catalytic cavity.

FIGURE 3

Molecular modulation of extinction. In low concentrations (thin orange arrows), the Ca²⁺/calmodulin complex activates CaN, which then dephosphorylates the I-1 (inhibitor 1), allowing PP1 to dephosphorylate CaMKII. CaN also dephosphorylates NMDARs (in blue) and AMPARs (in green) through AKAPs leading to AMPARs endocytosis, thus promoting LTD induction. NMDAR stimulation that induce LTD may also activate CaMKII, which elicits the phosphorylation of the AMPARs at residue S567 of the GluA1 subunit, propitiating their removal to the extra-synaptic space. CaN dephosphorylates CREB and the NFAT transcription factors as well. High concentrations of Ca²⁺ (thick orange arrows) activate kinases such as PKC and PKA, ROS and RCAN1 may act as CaN endogenous inhibitors. Arrows indicate activation while T arrows indicate inhibition either by phosphorylation or dephosphorylation. I-1: inhibitor 1; PP1: protein phosphatase 1; NFAT: nuclear factor of activated T-cells; CREB: cAMP response element binding; AKAP: A-Kinase Anchoring Protein; ROS: reactive oxygen species; PKA: protein kinase A; PKC: protein kinase C.