Relapse-Associated Transient Synaptic Potentiation Requires Integrin-Mediated Activation of Focal Adhesion Kinase and Cofilin in D1-Expressing Neurons.

Autor: Garcia-Keller C; Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425 garciake@musc.edu kalivasp@musc.edu., Scofield MD; Department of Anesthesiology, Medical University of South Carolina, Charleston, South Carolina 29425., Neuhofer D; Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425., Varanasi S; Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425., Reeves MT; Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425., Hughes B; Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425., Anderson E; Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425., Richie CT; Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland 21224., Mejias-Aponte C; Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland 21224., Pickel J; Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland 20892., Hope BT; Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland 21224., Harvey BK; Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland 21224., Cowan CW; Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425., Kalivas PW; Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425 garciake@musc.edu kalivasp@musc.edu.
Jazyk: angličtina
Zdroj: The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2020 Oct 28; Vol. 40 (44), pp. 8463-8477. Date of Electronic Publication: 2020 Oct 13.
DOI: 10.1523/JNEUROSCI.2666-19.2020
Abstrakt: Relapse to drug use can be initiated by drug-associated cues. The intensity of cue-induced drug seeking in rodent models correlates with the induction of transient synaptic potentiation (t-SP) at glutamatergic synapses in the nucleus accumbens core (NAcore). Matrix metalloproteinases (MMPs) are inducible endopeptidases that degrade extracellular matrix (ECM) proteins, and reveal tripeptide Arginine-Glycine-Aspartate (RGD) domains that bind and signal through integrins. Integrins are heterodimeric receptors composed of αβ subunits, and a primary signaling kinase is focal adhesion kinase (FAK). We previously showed that MMP activation is necessary for and potentiates cued reinstatement of cocaine seeking, and MMP-induced catalysis stimulates β3-integrins to induce t-SP. Here, we determined whether β3-integrin signaling through FAK and cofilin (actin depolymerization factor) is necessary to promote synaptic growth during t-SP. Using a small molecule inhibitor to prevent FAK activation, we blocked cued-induced cocaine reinstatement and increased spine head diameter (d h ). Immunohistochemistry on NAcore labeled spines with ChR2-EYFP virus, showed increased immunoreactivity of phosphorylation of FAK (p-FAK) and p-cofilin in dendrites of reinstated animals compared with extinguished and yoked saline, and the p-FAK and cofilin depended on β3-integrin signaling. Next, male and female transgenic rats were used to selectively label D1 or D2 neurons with ChR2-mCherry. We found that p-FAK was increased during drug seeking in both D1 and D2-medium spiny neurons (MSNs), but increased p-cofilin was observed only in D1-MSNs. These data indicate that β3-integrin, FAK and cofilin constitute a signaling pathway downstream of MMP activation that is involved in promoting the transient synaptic enlargement in D1-MSNs induced during reinstated cocaine by drug-paired cues. SIGNIFICANCE STATEMENT Drug-associated cues precipitate relapse, which is correlated with transient synaptic enlargement in the accumbens core. We showed that cocaine cue-induced synaptic enlargement depends on matrix metalloprotease signaling in the extracellular matrix (ECM) through β3-integrin to activate focal adhesion kinase (FAK) and phosphorylate the actin binding protein cofilin. The nucleus accumbens core (NAcore) contains two predominate neuronal subtypes selectively expressing either D1-dopamine or D2-dopamine receptors. We used transgenic rats to study each cell type and found that cue-induced signaling through cofilin phosphorylation occurred only in D1-expressing neurons. Thus, cocaine-paired cues initiate cocaine reinstatement and synaptic enlargement through a signaling cascade selectively in D1-expressing neurons requiring ECM stimulation of β3-integrin-mediated phosphorylation of FAK (p-FAK) and cofilin.
(Copyright © 2020 the authors.)
Databáze: MEDLINE
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