WAVE1 in neurons expressing the D1 dopamine receptor regulates cellular and behavioral actions of cocaine

Abstract

Wiskott-Aldrich syndrome protein (WASP) family verprolin homologous protein 1 (WAVE1) regulates actin-related protein 2/3 (Arp2/3) complex-mediated actin polymerization. Our previous studies have found WAVE1 to be inhibited by Cdk5-mediated phosphorylation in brain and to play a role in the regulation of dendritic spine morphology. Here we report that mice in which WAVE1 was knocked out (KO) in neurons expressing the D1 dopamine receptor (D1-KO), but not mice where WAVE1 was knocked out in neurons expressing the D2 dopamine receptor (D2-KO), exhibited a significant decrease in place preference associated with cocaine. In contrast to wild-type (WT) and WAVE1 D2-KO mice, cocaine-induced sensitized locomotor behavior was not maintained in WAVE1 D1-KO mice. After chronic cocaine administration and following withdrawal, an acute cocaine challenge induced WAVE1 activation in striatum, which was assessed by dephosphorylation. The cocaine-induced WAVE1 dephosphorylation was attenuated by coadministration of either a D1 dopamine receptor or NMDA glutamate receptor antagonist. Upon an acute challenge of cocaine following chronic cocaine exposure and withdrawal, we also observed in WT, but not in WAVE1 D1-KO mice, a decrease in dendritic spine density and a decrease in the frequency of excitatory postsynaptic AMPA receptor currents in medium spiny projection neurons expressing the D1 dopamine receptor (D1-MSNs) in the nucleus accumbens. These results suggest that WAVE1 is involved selectively in D1-MSNs in cocaine-evoked neuronal activitymediated feedback regulation of glutamatergic synapses.W iskott-Aldrich syndrome protein (WASP) family verprolin homologous protein (WAVE) initiates de novo actin polymerization through its ability to activate the actin-related protein 2/3 (Arp2/3) complex (1). Three members of the family (WAVE1-3) exist, with WAVE1 being highly expressed in brain (2). WAVE1 was purified from bovine or rat brain as part of a heteropentameric protein complex together with PIR121 [also called cytoplasmic FMR1-interacting protein 2, (Cyfip2)], Nck-associated protein 1 (Nckap1), Abl-interactor 2 (Abi2), and HSPC300 (3, 4). Whereas WAVE1 plays a key role in Arp2/3 complex binding and actin polymerization, other protein components in the complex are important for its subcellular localization and interaction with upstream ligands or activators (5, 6).In our initial study in striatum, the WAVE1 complex was found to interact with p35, the regulatory subunit of cyclin-dependent kinase 5 (Cdk5) (4). Phosphorylation of WAVE1 at Ser310, Ser397, and Ser441 by Cdk5/p35, in the complex purified from rat brain, or with recombinant WAVE1, resulted in inhibition of actin polymerization in vitro (4). We also observed that the stoichiometry of WAVE1 phosphorylation by Cdk5 is high in brain, suggestive of the protein being largely inactive under basal conditions (4). However, studies using mouse striatal slices indicated that WAVE1 can be dephosphorylated at all three Cdk5 sites and thereby activated upon stimulation of D1 dopa...

Different roles of Rac1 in the acquisition and extinction of methamphetamine-associated contextual memory in the nucleus accumbens

“…Our results indicate that Rac1 was mainly responsible for METH-induced spine plasticity in D1-MSNs. A recent study demonstrated that conditional knockout of WAVE1 in D1-MSNs but not D2-MSNs attenuated cocaine-induced CPP 72. Morover, another study revealed that the activation of Rap1 in D1-MSNs contributed to cocaine-induced CPP 73.…”

Electroacupuncture prevents cocaine-induced conditioned place preference reinstatement and attenuates ΔFosB and GluR2 expression

“…Dendritic spine density in the NAc core and shell was markedly increased by cocaine (30 mg/kg per day, i.p.) given for 5 consecutive days followed by 2 injection-free days for 4 weeks in total 41 , while a lower dosage (15 mg/kg per day for 8 consecutive days) increased spine density only in the shell 42 and in another study, cocaine (15 mg/kg per day for 14 consecutive days) induced significant increases in dendritic spine density in the NAc core but had only minimal effects in the NAc shell 43 . Based on the results of these studies, we decided to test the effects of cocaine at the dose of 30 mg/kg (or saline) daily for 14 days (see Fig.…”

A Maternal Transcription Factor, Junction Mediating and Regulatory Protein is Required for Preimplantation Development in the Mouse

“…Although the molecular machinery that regulates actin polymerization in neurons is not fully characterized, different actin nucleators, including the Arp2/3 complex (Zuo et al, 2017) and its NPFs N-WASP (Pinyol, 2007; Ceglia et al, 2017), WAVE1 (Firat-Karalar & Welch, 2011) and WAVE 2 (Hoeng et al, 2008), as well as the tandem actin-monomer-binding nucleator Cordon-bleu (Coutts et al, 2009) were shown to positively regulate the stages of neuronal development through their role in growth cone formation and dynamics. In contrast, we found that knockout of CA (Arp2/3 binding site) on JMY gene obviously affected blastocystformation.…”

“…One possibility was that JMY acts as an upstream effector of ZGA genes such as Hsp70.1 , eIF-1A , mUerv-l and MTIA . Actin-nucleating proteins are regulated by small GTPases, protein–protein interactions, and/or posttranslational modifications, and it is likely that JMY is also regulated by similar mechanisms (Ceglia et al., 2017). Another intriguing question is why JMY combines two uniquely different cellular functions-transcriptional regulations and actin assembly in one protein.…”

“…Another intriguing question is why JMY combines two uniquely different cellular functions-transcriptional regulations and actin assembly in one protein. Given the emeging role of nuclear actin in transcription regulation (Ceglia et al, 2017), it can be speculated that JMY acts as a molecular link between the actin cytoskeleton and the transcriptional machinery. It will be important to examine the transcription- and actin-related functions of JMY in cellular processes, including early embryo development.…”