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Exp. Mol. Med., 10 February 2025 | https://doi.org/10.1038/s12276-025-01399-z GluN2B-mediated regulation of silent synapses for receptor specification and addiction memory

Hyun Jin Kim ^1,2,8, Sangjun Lee ^1,3,8, Gyu Hyun Kim ^4,5, Kibong Sung ¹, Taesik Yoo ¹, Jung Hyun Pyo ¹, Hee-Jung Jo ¹, Sanghyeon Lee ⁶, Hyun-Young Lee ¹, Jung Hoon Jung⁷, Kea Joo Lee ⁴ and Joung-Hun Kim ^1,*

¹Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea.
²Salk Institute for Biological Studies, La Jolla, CA, USA.
³Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.

⁴Neural Circuits Research Group, Korea Brain Research Institute, Daegu, Republic of Korea.
⁵Department of Neuroscience, Korea University College of Medicine, Seoul, Republic of Korea.
⁶Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
⁷College of Pharmacy, Keimyung University, Daegu, Republic of Korea.
⁸These authors contributed equally: Hyun Jin Kim, Sangjun Lee.

^*Corresponding author: correspondence to Joung-Hun Kim

Abstract

Psychostimulants, including cocaine, elicit stereotyped, addictive behaviors. The reemergence of silent synapses containing only NMDA-type glutamate receptors is a critical mediator of addiction memory and seeking behaviors. Despite the predominant abundance of GluN2B-containing NMDA-type glutamate receptors in silent synapses, their operational mechanisms are not fully understood. Here, using conditional depletion/deletion of GluN2B in D1-expressing accumbal medium spiny neurons, we examined the synaptic and behavioral actions that silent synapses incur after repeated exposure to cocaine. GluN2B ablation reduces the proportion of silent synapses, but some of them can persist by substitution with GluN2C, which drives the aberrantly facilitated synaptic incorporation of calcium-impermeable AMPA-type glutamate receptors (AMPARs). The resulting precocious maturation of silent synapses impairs addiction memory but increases locomotor activity, both of which can be normalized by the blockade of calcium-impermeable AMPAR trafficking. Collectively, GluN2B supports the competence of cocaine-induced silent synapses to specify the subunit composition of AMPARs and thereby the expression of addiction memory and related behaviors.

논문정보

형식Research article
게재일2025년 02월 (BRIC 등록일 2025-02-12)
연구진국내(교신)+국외 연구진
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