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WAVE1 in Neurons Expressing the D1 Dopamine Receptor Regulates Cellular and Behavioral Actions of Cocaine

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WAVE1 in Neurons Expressing the D1 Dopamine Receptor Regulates Cellular and Behavioral Actions of Cocaine WAVE1 in neurons expressing the D1 dopamine receptor regulates cellular and behavioral actions of cocaine Ilaria Cegliaa,1, Ko-Woon Leea,1, Michael E. Cahillb,1, Steven M. Gravesc, David Dietzd, Dalton J. Surmeierc, Eric J. Nestlerb, Angus C. Nairna,e, Paul Greengarda,2, and Yong Kima,2 aLaboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065; bFishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029; cDepartment of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; dDepartment of Pharmacology and Toxicology, Research Institute on Addictions, Program in Neuroscience, State University of New York at Buffalo, Buffalo, NY 14214; and eDepartment of Psychiatry, Yale University School of Medicine, New Haven, CT 06508 Contributed by Paul Greengard, December 23, 2016 (sent for review October 26, 2016; reviewed by Huda Akil and Solomon H. Snyder) Wiskott-Aldrich syndrome protein (WASP) family verprolin homolo- upon stimulation of D1 dopamine and of NMDA glutamate re- + gous protein 1 (WAVE1) regulates actin-related protein 2/3 (Arp2/3) ceptors, acting through cAMP- and Ca2 -mediated activation of complex-mediated actin polymerization. Our previous studies have protein phosphatase 2A and 2B, respectively (4, 7). These results found WAVE1 to be inhibited by Cdk5-mediated phosphorylation indicate that WAVE1 is a neuronal activity-regulated phospho- in brain and to play a role in the regulation of dendritic spine mor- protein in the striatum. phology. Here we report that mice in which WAVE1 was knocked out We previously identified a pivotal role for Cdk5/p35 in cocaine- (KO) in neurons expressing the D1 dopamine receptor (D1-KO), but induced adaptive changes in brain (8). Cocaine is a highly addictive not mice where WAVE1 was knocked out in neurons expressing the psychostimulant that exerts its effects on brain reward regions such D2 dopamine receptor (D2-KO), exhibited a significant decrease in as the nucleus accumbens (NAc), a ventral part of the striatum (9– place preference associated with cocaine. In contrast to wild-type 11). The NAc receives dopaminergic input from the ventral teg- (WT) and WAVE1 D2-KO mice, cocaine-induced sensitized locomotor mental area (VTA) and glutamatergic inputs from the medial behavior was not maintained in WAVE1 D1-KO mice. After chronic prefrontal cortex (mPFC), hippocampus, and amygdala, among cocaine administration and following withdrawal, an acute cocaine other regions (12). Cocaine elevates synaptic levels of dopamine by challenge induced WAVE1 activation in striatum, which was assessed blocking reuptake of dopamine into presynaptic terminals (13, 14). by dephosphorylation. The cocaine-induced WAVE1 dephosphoryla- However, chronic exposure to cocaine dampens dopamine signaling tion was attenuated by coadministration of either a D1 dopamine through increases in ΔFosB and Cdk5/p35 (8). Cdk5/p35 phos- receptor or NMDA glutamate receptor antagonist. Upon an acute phorylates Thr75 of DARPP-32, a master regulator of dopamine challenge of cocaine following chronic cocaine exposure and with- signaling in striatal medium spiny projection neurons (MSNs), and drawal, we also observed in WT, but not in WAVE1 D1-KO mice, a thereby negatively regulates DARPP-32 function (15). Chronic decrease in dendritic spine density and a decrease in the frequency of exposure to cocaine also changes glutamatergic synapses in the excitatory postsynaptic AMPA receptor currents in medium spiny projection neurons expressing the D1 dopamine receptor (D1-MSNs) Significance in the nucleus accumbens. These results suggest that WAVE1 is involved selectively in D1-MSNs in cocaine-evoked neuronal activity- Cocaine-induced synaptic plasticity in the nucleus accumbens is mediated feedback regulation of glutamatergic synapses. implicated in neural adaptations that underlie addiction. Here we demonstrate that Wiskott-Aldrich syndrome protein (WASP) WAVE1 | cocaine | striatum | medium spiny projection neurons | Cdk5 family verprolin homologous protein 1 (WAVE1) plays a selective role in medium spiny projection neurons that express D1 dopa- iskott-Aldrich syndrome protein (WASP) family verprolin mine receptors (D1-MSNs) in the cellular and behavioral actions Whomologous protein (WAVE) initiates de novo actin poly- of cocaine. Our results suggest that chronic exposure to cocaine, merization through its ability to activate the actin-related protein 2/3 followed by withdrawal, potentiates the signaling capacity of (Arp2/3) complex (1). Three members of the family (WAVE1–3) D1 dopamine and NMDA glutamate receptors, allowing WAVE1 exist, with WAVE1 being highly expressed in brain (2). WAVE1 activation in response to an acute cocaine challenge. WAVE1 was purified from bovine or rat brain as part of a heteropentameric activation is associated with morphological and functional de- protein complex together with PIR121 [also called cytoplasmic creases in glutamatergic synapses on D1-MSNs. Thus, we pro- FMR1-interacting protein 2, (Cyfip2)], Nck-associated protein 1 pose that WAVE1 is involved in a negative feedback mechanism (Nckap1), Abl-interactor 2 (Abi2), and HSPC300 (3, 4). Whereas of regulation of glutamatergic synapses as a part of the process WAVE1 plays a key role in Arp2/3 complex binding and actin of cocaine-induced synaptic plasticity. polymerization, other protein components in the complex are im- portant for its subcellular localization and interaction with upstream Author contributions: I.C., K.-W.L., M.E.C., S.M.G., D.D., D.J.S., E.J.N., A.C.N., P.G., and Y.K. ligands or activators (5, 6). designed research; I.C., K.-W.L., M.E.C., S.M.G., D.D., and Y.K. performed research; Y.K. contributed new reagents/analytic tools; I.C., K.-W.L., M.E.C., S.M.G., and Y.K. analyzed In our initial study in striatum, the WAVE1 complex was found data; and I.C., M.E.C., S.M.G., D.J.S., E.J.N., A.C.N., P.G., and Y.K. wrote the paper. NEUROSCIENCE to interact with p35, the regulatory subunit of cyclin-dependent Reviewers: H.A., University of Michigan; and S.H.S., Johns Hopkins University School kinase 5 (Cdk5) (4). Phosphorylation of WAVE1 at Ser310, Ser397, of Medicine. and Ser441 by Cdk5/p35, in the complex purified from rat brain, or The authors declare no conflict of interest. with recombinant WAVE1, resulted in inhibition of actin poly- Freely available online through the PNAS open access option. merization in vitro (4). We also observed that the stoichiometry of 1I.C., K.-W.L., and M.E.C. contributed equally to this work. WAVE1 phosphorylation by Cdk5 is high in brain, suggestive of the 2To whom correspondence may be addressed. Email: [email protected] or protein being largely inactive under basal conditions (4). However, [email protected]. studies using mouse striatal slices indicated that WAVE1 can be This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. dephosphorylated at all three Cdk5 sites and thereby activated 1073/pnas.1621185114/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1621185114 PNAS | February 7, 2017 | vol. 114 | no. 6 | 1395–1400 Downloaded by guest on September 25, 2021 NAc, including increasing dendritic spine density (9, 10, 16, 17). We showed that a Cdk5 inhibitor attenuated baseline dendritic spine density as well as cocaine-induced dendritic spine outgrowth in NAc core and shell, suggesting an involvement of Cdk5 in the regulation of dendritic spine density (18). WAVE1 is also known to regulate dendritic spine morphology (4). In the present study, we investigated the function of WAVE1 in the cellular and behavioral responses to cocaine. We found a critical role of WAVE1 expressed in a subpopulation of MSNs in cocaine-induced feedback regula- tion of dendritic spine density, maintenance of cocaine-induced locomotor sensitization, and cocaine reward. Results Expression of WAVE1 in D1- and D2-MSNs and Generation of Cell- Type–Specific WAVE1 KO Mice. The WAVE1 complex is highly expressed in the forebrain, including cerebral cortex, hippocampus, striatum, and thalamus, and this expression pattern is well correlated with that of p35 (Fig. S1A) (2). MSNs, the major neuronal type in the Fig. 1. Cocaine-induced CPP and locomotor sensitization in WAVE1 D1- or D2- KO mice. (A and B) Cocaine-associated place preference in D1-KO mice (A)or striatum, are largely segregated into two distinct subpopulations D2-KO mice (B) and WT mice was assessed using a “regular” CPP test with co- expressing high levels of either dopamine D1 receptor (D1) or D2 caine (7.5 mg/kg, i.p.): WT versus D1-KO mice [t = 2.663, *P < 0.05, n = 17 (WT), – 31 receptor (D2) (19 21). We used bacterial artificial chromosome 16 (D1-KO)] and WT versus D2-KO mice [n = 10 (WT), 10 (D2-KO)]. (C and D) (BAC) transgenic mice expressing EGFP under the control of D1 “Sensitization” CPP was assessed in D1-KO (C)orD2-KO(D)andWTmicein (Drd1) or D2 (Drd2) promoters and examined the expression of which cocaine was administered (15 mg/kg) for 7 consecutive days followed by a WAVE1 and EGFP in D1- and D2-MSNs. Similar levels of WAVE1 5-d withdrawal (WD). Preference for a low dose of cocaine (5 mg/kg) was then = < = immunostaining were observed in both D1- and D2-MSNs (Fig. S1 B assessed: WT versus D1-KO mice [t15 2.271, *P 0.05, n 7 (WT), 10 (D1-KO)] and C). Anatomically, D1-MSNs and D2-MSNs in dorsal striatum and WT versus D2-KO mice [n = 8 (WT), 8 (D2-KO)]. (E and F)WTmiceand project to distinct brain areas (22) but projections of D1-MSNs and WAVE1 D1-KO mice (E)orD2-KOmice(F) were treated daily with saline for 2 d. Cocaine (10 mg/kg, i.p.) was administered for 10 consecutive days. After chronic D2-MSNs from the NAc are more overlapping and remain to be cocaine administration, WT and D1-KO mice were divided into two groups (n = further defined (11, 23).
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