Intra- and Extracellular Pillars of a Unifying Framework for Homeostatic Plasticity: A Crosstalk Between Metabotropic Receptors and Extracellular Matrix.

Lorenzo A Cingolani,Carmela Vitale,Alexander Dityatev

doi:10.3389/fncel.2019.00513

Abstract

In the face of chronic changes in incoming sensory inputs, neuronal networks are capable of maintaining stable conditions of electrical activity over prolonged periods of time by adjusting synaptic strength, to amplify or dampen incoming inputs [homeostatic synaptic plasticity (HSP)], or by altering the intrinsic excitability of individual neurons [homeostatic intrinsic plasticity (HIP)]. Emerging evidence suggests a synergistic interplay between extracellular matrix (ECM) and metabotropic receptors in both forms of homeostatic plasticity. Activation of dopaminergic, serotonergic, or glutamate metabotropic receptors stimulates intracellular signaling through calmodulin-dependent protein kinase II, protein kinase A, protein kinase C, and inositol trisphosphate receptors, and induces changes in expression of ECM molecules and proteolysis of both ECM molecules (lecticans) and ECM receptors (NPR, CD44). The resulting remodeling of perisynaptic and synaptic ECM provides permissive conditions for HSP and plays an instructive role by recruiting additional signaling cascades, such as those through metabotropic glutamate receptors and integrins. The superimposition of all these signaling events determines intracellular and diffusional trafficking of ionotropic glutamate receptors, resulting in HSP and modulation of conditions for inducing Hebbian synaptic plasticity (i.e., metaplasticity). It also controls cell-surface delivery and activity of voltage- and Ca2+-gated ion channels, resulting in HIP. These mechanisms may modify epileptogenesis and become a target for therapeutic interventions.

Highlights

Homeostatic plasticity enables neurons to stabilize network activity within an optimal dynamic range over prolonged periods of time, thereby playing a fundamental neuroprotective role during pathological conditions that tend to alter function and integrity of neuronal networks
In addition to extensive analyses of ion channel trafficking and intracellular signaling pathways involved in the different forms of homeostatic plasticity, several studies have revealed the importance of synaptic extracellular matrix (ECM) molecules, such as neuronal activity-regulated pentraxin (Narp) (Chang et al, 2010), and major ECM receptors such as β3 integrin (Cingolani et al, 2008; McGeachie et al, 2012)
(3) This results in activation of extracellular proteinases [tumor necrosis factor-α-converting enzyme (TACE), disintegrin and metalloprotease with thrombospondin motifs 4/5 (ADAMTS4/5), matrix metalloproteinase 9 (MMP9)], which (4) may process ECM molecules or (5) ECM receptors (NPR, CD44), enabling synaptic modifications as well as (6) signaling back through modulation of G protein-coupled receptors (GPCRs) and (7) additional intracellular signaling events

Summary

Introduction

Homeostatic plasticity enables neurons to stabilize network activity within an optimal dynamic range over prolonged periods of time, thereby playing a fundamental neuroprotective role during pathological conditions that tend to alter function and integrity of neuronal networks. In addition to extensive analyses of ion channel trafficking and intracellular signaling pathways involved in the different forms of homeostatic plasticity, several studies have revealed the importance of synaptic extracellular matrix (ECM) molecules, such as neuronal activity-regulated pentraxin (Narp) (Chang et al, 2010), and major ECM receptors such as β3 integrin (Cingolani et al, 2008; McGeachie et al, 2012).

Results

Conclusion