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CCL2/CCR2 Contributes to the Altered Excitatory-inhibitory Synaptic Balance in the Nucleus Accumbens Shell Following Peripheral Nerve Injury-induced Neuropathic Pain

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Abstract

The medium spiny neurons (MSNs) in the nucleus accumbens (NAc) integrate excitatory and inhibitory synaptic inputs and gate motivational and emotional behavior output. Here we report that the relative intensity of excitatory and inhibitory synaptic inputs to MSNs of the NAc shell was decreased in mice with neuropathic pain induced by spinal nerve ligation (SNL). SNL increased the frequency, but not the amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs), and decreased both the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in the MSNs. SNL also decreased the paired-pulse ratio (PPR) of evoked IPSCs but increased the PPR of evoked EPSCs. Moreover, acute bath application of C–C motif chemokine ligand 2 (CCL2) increased the frequency and amplitude of sIPSCs and sEPSCs in the MSNs, and especially strengthened the amplitude of N-methyl-D-aspartate receptor (NMDAR)-mediated miniature EPSCs. Further Ccl2 overexpression in the NAc in vivo decreased the peak amplitude of the sEPSC/sIPSC ratio. Finally, Ccr2 knock-down improved the impaired induction of NMDAR-dependent long-term depression (LTD) in the NAc after SNL. These results suggest that CCL2/CCR2 signaling plays a role in the integration of excitatory/inhibitory synaptic transmission and leads to an increase of the LTD induction threshold at the synapses of MSNs during neuropathic pain.

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Acknowledgements

This work was supported by Grants from the National Natural Science Foundation of China (32030048, 31871064, and 31671091).

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Authors and Affiliations

  1. Institute of Pain Medicine and Special Environmental Medicine, Nantong University, Nantong, 226019, China

    Xiao-Bo Wu, Qian Zhu & Yong-Jing Gao

  2. Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China

    Yong-Jing Gao

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Correspondence to Xiao-Bo Wu or Yong-Jing Gao.

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Wu, XB., Zhu, Q. & Gao, YJ. CCL2/CCR2 Contributes to the Altered Excitatory-inhibitory Synaptic Balance in the Nucleus Accumbens Shell Following Peripheral Nerve Injury-induced Neuropathic Pain. Neurosci. Bull. 37, 921–933 (2021). https://doi.org/10.1007/s12264-021-00697-6

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  • DOI: https://doi.org/10.1007/s12264-021-00697-6

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