mDia and ROCK Mediate Actin-Dependent Presynaptic Remodeling Regulating Synaptic Efficacy and Anxiety

Abstract

Here, we show neuronal inactivation-induced presynaptic remodeling and involvement of the mammalian homolog of Diaphanous (mDia) and Rho-associated coiled-coil-containing kinase (ROCK), Rho-regulated modulators of actin and myosin, in this process. We find that social isolation induces inactivation of nucleus accumbens (NAc) neurons associated with elevated anxiety-like behavior, and that mDia in NAc neurons is essential in this process. Upon inactivation of cultured neurons, mDia induces circumferential actin filaments around the edge of the synaptic cleft, which contract the presynaptic terminals in a ROCK-dependent manner. Social isolation induces similar mDia-dependent presynaptic contraction at GABAergic synapses from NAc neurons in the ventral tegmental area (VTA) associated with reduced synaptic efficacy. Optogenetic stimulation of NAc neurons rescues the anxiety phenotype, and injection of a specific ROCK inhibitor, Y-27632, into the VTA reverses both presynaptic contraction and the behavioral phenotype. mDia-ROCK signaling thus mediates actin-dependent presynaptic remodeling in inactivated NAc neurons, which underlies synaptic plasticity in emotional behavioral responses.

Semaphorin4D Induces Inhibitory Synapse Formation by Rapid Stabilization of Presynaptic Boutons via MET Coactivation

“…As the actin depolymerization pathway downstream of Sema4D/PlexinB1 signaling via MET is mediated via a reduction of intracellular RhoA activity (Swiercz et al, 2008;Sun et al, 2012), we tested whether stabilization of inhibitory boutons could also be achieved by directly reducing ROCK activity, a well known downstream effector of RhoA (Amano et al, 2010). We found that treatment with the specific ROCK inhibitor Y-27632 (Deguchi et al, 2016) resulted in an increase in the density of stabilizing boutons in our slices (Fig. 7L), without affecting the other subclasses of boutons.…”

The effects of tamoxifen on mouse behavior

“…Although tamoxifen has been used in mouse models for a long time, the effects of tamoxifen have not been researched . In the isolation model, isolation can result in hyperactivity and depression .…”

“…All the above mentioned results were in mice that were not subjected to mouse models or mutagenesis. In the literature, many experiments are designed to make mice into animal models before or after tamoxifen administration . Therefore, we designed protocols to explore whether tamoxifen could promote or prevent behavioral alterations after the mouse model.…”

Microtubules (MT) a key target in oncology: mathematical modeling of anti-MT agents on cell migration

“…Thus, in our model when a microtubule is depolymerizing, the Rho protein is activated leading to a Rac inactivation. The reaction terms then read: (15) with, τ Rac→Rac the intrinsic activation rate, τ Rac→Rac the inactivation rate, γ Rac , K Rac parameters for the positive feedback. The function k 0 is used to know if a microtubule is polymerizing or not:…”

“…Rho regulates actomyosin formation through mammalian homolog of Diaphanous (mDia) and Rho-associated coiled-coil-containing kinase (ROCK) [37]. The mDia protein promotes actin nucleation and polymerization [15] while ROCK activates myosin light chain and cooperates with mDia to form actomyosin bundles and generate contractility [37]. In this paper, Rho is assumed to activate ROCK at the rear of the cell to regulate actomyosin contractility.…”