Neuroligins facilitate the development of bone cancer pain via regulating synaptic transmission: an experimental study

Xianqiao Xie; Yang Li; Shanchun Su; Xiaohui Li; Xueqin Xu; Yan Gao; Minjing Peng; Changbin Ke

doi:10.1016/j.bjane.2023.02.001

Original Investigation

Neuroligins facilitate the development of bone cancer pain via regulating synaptic transmission: an experimental study

Xianqiao Xie, Yang Li, Shanchun Su, Xiaohui Li, Xueqin Xu, Yan Gao, Minjing Peng, Changbin Ke

http://dx.doi.org/10.1016/j.bjane.2023.02.001 Braz J Anesthesiol, Ahead of Print, 2023

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Abstract

Background

The underlying mechanism of chronic pain involves the plasticity in synaptic receptors and neurotransmitters. This study aimed to investigate potential roles of Neuroligins (NLs) within the spinal dorsal horn of rats in a newly established Bone Cancer Pain (BCP) model. The objective was to explore the mechanism of neuroligin involved in the occurrence and development of bone cancer pain.

Methods

Using our rat BCP model, we assessed pain hypersensitivity over time. Quantitative real-time polymerase chain reaction and Western blot analysis were performed to investigate NL expression, and NLs were overexpressed in the rat spinal cord using lentiviral vectors. Immunofluorescence staining and whole-cell patch-clamp recordings were deployed to investigate the role of NLs in the development of BCP.

Results

We observed reduced expression levels of NL1 and NL2, but not of NL3, within the rat spinal cord, which were found to be associated with and essential for the development of BCP in our model. Accordingly, NL1 or NL2 overexpression in the spinal cord alleviated mechanical hypersensitivity of rats. Electrophysiological experiments indicated that NL1 and NL2 are involved in BCP via regulating γ-aminobutyric acid-ergic interneuronal synapses and the activity of glutamatergic interneuronal synapses, respectively.

Conclusions

Our observations unravel the role of NLs in cancer-related chronic pain and further suggest that inhibitory mechanisms are central features of BCP in the spinal dorsal horn. These results provide a new perspective and basis for subsequent studies elucidating the onset and progression of BCP.

Keywords

Cancer pain, GABAergic, Glutamatergic, Neuroligins, Synaptic transmission

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Neuroligins determine synapse maturation and function

Neuron, 51 (2006), pp. 741-754
2

S Baudouin, P. Scheiffele

SnapShot: Neuroligin-neurexin complexes

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Postsynaptic scaffolding molecules modulate the localization of neuroligins

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M Hoon, T Soykan, B Falkenburger, et al.

Neuroligin-4 is localized to glycinergic postsynapses and regulates inhibition in the retina

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T-B Lin, C-Y Lai, M-C Hsieh, et al.

Neuropathic allodynia involves spinal neurexin-1β-dependent neuroligin-1/postsynaptic density-95/NR2B cascade in rats

Anesthesiology, 123 (2015), pp. 909-926
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M Mondin, V Labrousse, E Hosy, et al.

Neurexin-neuroligin adhesions capture surface-diffusing AMPA receptors through PSD-95 scaffolds

J Neurosci, 31 (2011), pp. 13500-13515
8

EC Budreck, OB Kwon, JH Jung, et al.

Neuroligin-1 controls synaptic abundance of NMDA-type glutamate receptors through extracellular coupling

Proc Natl Acad Sci U S A, 110 (2013), pp. 725-730
9

G Choii, J. Ko

Gephyrin: a central GABAergic synapse organizer

Exp Mol Med, 47 (2015), p. e158
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R Antonelli, R Pizzarelli, A Pedroni, et al.

Pin1-dependent signalling negatively affects GABAergic transmission by modulating neuroligin2/gephyrin interaction

Nat Commun, 5 (2014), p. 5066
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SL Shipman, E Schnell, T Hirai, Chen BS, KW Roche, RA. Nicoll

Functional dependence of neuroligin on a new non-PDZ intracellular domain

Nat Neurosci, 14 (2011), pp. 718-726
12

SG Marro, S Chanda, N Yang, JA Janas, G Valperga, J Trotter, et al.

Neuroligin-4 regulates excitatory synaptic transmission in human neurons

Neuron, 103 (2019), pp. 617-626

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13

R Guo, H Li, X Li, et al.

Increased neuroligin 2 levels in the postsynaptic membrane in spinal dorsal horn may contribute to postoperative pain

Neuroscience, 382 (2018), pp. 14-22
14

T Dolique, A Favereaux, O Roca-Lapirot, et al.

Unexpected association of the "inhibitory" neuroligin 2 with excitatory PSD95 in neuropathic pain

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15

JY Zhao, XL Duan, L Yang, et al.

Activity-dependent synaptic recruitment of neuroligin 1 in spinal dorsal horn contributed to inflammatory pain

Neuroscience, 388 (2018), pp. 1-10
16

D Spicarova, P Adamek, N Kalynovska, P Mrozkova, J. Palecek

TRPV1 receptor inhibition decreases CCL2-induced hyperalgesia

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Protocadherin20 promotes excitatory synaptogenesis in dorsal horn and contributes to bone cancer pain[J]

Neuropharmacology, 75 (2013), pp. 181-190
18

C Ke, F Gao, X Tian, C Li, D Shi, W He, et al.

Slit2/Robo1 Mediation of Synaptic Plasticity Contributes to Bone Cancer Pain

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22

P Jedlicka, M Vnencak, DD Krueger, T Jungenitz, N Brose, SW. Schwarzacher

Neuroligin-1 regulates excitatory synaptic transmission, LTP and EPSP-spike coupling in the dentate gyrus in vivo

Brain Struct Funct, 220 (2015), pp. 47-58
23

SL Shipman, RA Nicoll

A subtype-specific function for the extracellular domain of neuroligin 1 in hippocampal LTP

Neuron, 76 (2012), pp. 309-316
24

B Chih, H Engelman, P. Scheiffele

Control of excitatory and inhibitory synapse formation by neuroligins

Science, 307 (2005), pp. 1324-1328
25

R Dahlhaus, RM Hines, BD Eadie, et al.

Overexpression of the cell adhesion protein neuroligin-1 induces learning deficits and impairs synaptic plasticity by altering the ratio of excitation to inhibition in the hippocampus

Hippocampus, 20 (2010), pp. 305-322
26

J Li, W Han, KA Pelkey, et al.

Molecular dissection of neuroligin 2 and slitrk3 reveals an essential framework for GABAergic synapse development

Neuron, 96 (2017), pp. 808-826

e808
27

JR Gibson, KM Huber, TC. Sudhof

Neuroligin-2 deletion selectively decreases inhibitory synaptic transmission originating from fast-spiking but not from somatostatin-positive interneurons

J Neurosci, 29 (2009), pp. 13883-13897
28

Q Q Xia, J Xu, TL Liao, J Yu, L Shi, J Xia, et al.

Neuroligins differentially mediate subtype-specific synapse formation in pyramidal neurons and interneurons

Neurosci Bull, 35 (2019), pp. 497-506
29

AA Chubykin, D Atasoy, MR Etherton, et al.

Activity-dependent validation of excitatory versus inhibitory synapses by neuroligin-1 versus neuroligin-2

Neuron, 54 (2007), pp. 919-931
30

SG Ravyts, JM Dzierzewski, SC Grah, et al.

Pain inconsistency and sleep in mid to late-life: the role of depression

Aging Ment Health, 23 (2019), pp. 1174-1179
31

MK. Nicholas

Depression in people with pain: There is still work to do Commentary on ‘Understanding the link between depression and pain’

Scand J Pain, 2 (2011), pp. 45-46
32

MK. Nicholas

Understanding the link between depression and pain

Scand J Pain, 2 (2011), pp. 45-46

[1] 1

F Varoqueaux, G Aramuni, RL Rawson, et al.

Neuroligins determine synapse maturation and function

Neuron, 51 (2006), pp. 741-754

[2] 2

S Baudouin, P. Scheiffele

SnapShot: Neuroligin-neurexin complexes

Cell, 141 (2010), p. 908

908 e901

[3] 3

JN Levinson, R Li, R Kang, H Moukhles, A El-Husseini, SX. Bamji

Postsynaptic scaffolding molecules modulate the localization of neuroligins

Neuroscience, 165 (2010), pp. 782-793

[4] 4

MA Bemben, SL Shipman, RA Nicoll, KW. Roche

The cellular and molecular landscape of neuroligins[J]

Trends Neurosciences, 38 (2015), pp. 496-505

[5] 5

M Hoon, T Soykan, B Falkenburger, et al.

Neuroligin-4 is localized to glycinergic postsynapses and regulates inhibition in the retina

Proc Natl Acad Sci U S A, 108 (2011), pp. 3053-3058

[6] 6

T-B Lin, C-Y Lai, M-C Hsieh, et al.

Neuropathic allodynia involves spinal neurexin-1β-dependent neuroligin-1/postsynaptic density-95/NR2B cascade in rats

Anesthesiology, 123 (2015), pp. 909-926

[7] 7

M Mondin, V Labrousse, E Hosy, et al.

Neurexin-neuroligin adhesions capture surface-diffusing AMPA receptors through PSD-95 scaffolds

J Neurosci, 31 (2011), pp. 13500-13515

[8] 8

EC Budreck, OB Kwon, JH Jung, et al.

Neuroligin-1 controls synaptic abundance of NMDA-type glutamate receptors through extracellular coupling

Proc Natl Acad Sci U S A, 110 (2013), pp. 725-730

[9] 9

G Choii, J. Ko

Gephyrin: a central GABAergic synapse organizer

Exp Mol Med, 47 (2015), p. e158

[10] 10

R Antonelli, R Pizzarelli, A Pedroni, et al.

Pin1-dependent signalling negatively affects GABAergic transmission by modulating neuroligin2/gephyrin interaction

Nat Commun, 5 (2014), p. 5066

[11] 11

SL Shipman, E Schnell, T Hirai, Chen BS, KW Roche, RA. Nicoll

Functional dependence of neuroligin on a new non-PDZ intracellular domain

Nat Neurosci, 14 (2011), pp. 718-726

[12] 12

SG Marro, S Chanda, N Yang, JA Janas, G Valperga, J Trotter, et al.

Neuroligin-4 regulates excitatory synaptic transmission in human neurons

Neuron, 103 (2019), pp. 617-626

e616

[13] 13

R Guo, H Li, X Li, et al.

Increased neuroligin 2 levels in the postsynaptic membrane in spinal dorsal horn may contribute to postoperative pain

Neuroscience, 382 (2018), pp. 14-22

[14] 14

T Dolique, A Favereaux, O Roca-Lapirot, et al.

Unexpected association of the "inhibitory" neuroligin 2 with excitatory PSD95 in neuropathic pain

Pain, 154 (2013), pp. 2529-2546

[15] 15

JY Zhao, XL Duan, L Yang, et al.

Activity-dependent synaptic recruitment of neuroligin 1 in spinal dorsal horn contributed to inflammatory pain

Neuroscience, 388 (2018), pp. 1-10

[16] 16

D Spicarova, P Adamek, N Kalynovska, P Mrozkova, J. Palecek

TRPV1 receptor inhibition decreases CCL2-induced hyperalgesia

Neuropharmacology, 81 (2014), pp. 75-84

[17] 17

C Ke, C Li, X Huang, F Cao, D Shi, W He, et al.

Protocadherin20 promotes excitatory synaptogenesis in dorsal horn and contributes to bone cancer pain[J]

Neuropharmacology, 75 (2013), pp. 181-190

[18] 18

C Ke, F Gao, X Tian, C Li, D Shi, W He, et al.

Slit2/Robo1 Mediation of Synaptic Plasticity Contributes to Bone Cancer Pain

Mol Neurobiol, 54 (2017), pp. 295-307

[19] 19

A Ghosh, ME. Greenberg

Distinct roles for bFGF and NT-3 in the regulation of cortical neurogenesis [J]

Neuron, 15 (1995), pp. 89-103

[20] 20

H Turkez, B Togar, A Di Stefano, N Taspınar, P. Sozio

Protective effects of cyclosativene on H2O2-induced injury in cultured rat primary cerebral cortex cells[J]

Cytotechnology (Dordrecht), 67 (2015), pp. 299-309

[21] 21

M Ashburner, CA Ball, JA Blake, et al.

Gene ontology: tool for the unification of biology. The Gene Ontology Consortium

Nat Genet, 25 (2000), pp. 25-29

[22] 22

P Jedlicka, M Vnencak, DD Krueger, T Jungenitz, N Brose, SW. Schwarzacher

Neuroligin-1 regulates excitatory synaptic transmission, LTP and EPSP-spike coupling in the dentate gyrus in vivo

Brain Struct Funct, 220 (2015), pp. 47-58

[23] 23

SL Shipman, RA Nicoll

A subtype-specific function for the extracellular domain of neuroligin 1 in hippocampal LTP

Neuron, 76 (2012), pp. 309-316

[24] 24

B Chih, H Engelman, P. Scheiffele

Control of excitatory and inhibitory synapse formation by neuroligins

Science, 307 (2005), pp. 1324-1328

[25] 25

R Dahlhaus, RM Hines, BD Eadie, et al.

Overexpression of the cell adhesion protein neuroligin-1 induces learning deficits and impairs synaptic plasticity by altering the ratio of excitation to inhibition in the hippocampus

Hippocampus, 20 (2010), pp. 305-322

[26] 26

J Li, W Han, KA Pelkey, et al.

Molecular dissection of neuroligin 2 and slitrk3 reveals an essential framework for GABAergic synapse development

Neuron, 96 (2017), pp. 808-826

e808

[27] 27

JR Gibson, KM Huber, TC. Sudhof

Neuroligin-2 deletion selectively decreases inhibitory synaptic transmission originating from fast-spiking but not from somatostatin-positive interneurons

J Neurosci, 29 (2009), pp. 13883-13897

[28] 28

Q Q Xia, J Xu, TL Liao, J Yu, L Shi, J Xia, et al.

Neuroligins differentially mediate subtype-specific synapse formation in pyramidal neurons and interneurons

Neurosci Bull, 35 (2019), pp. 497-506

[29] 29

AA Chubykin, D Atasoy, MR Etherton, et al.

Activity-dependent validation of excitatory versus inhibitory synapses by neuroligin-1 versus neuroligin-2

Neuron, 54 (2007), pp. 919-931

[30] 30

SG Ravyts, JM Dzierzewski, SC Grah, et al.

Pain inconsistency and sleep in mid to late-life: the role of depression

Aging Ment Health, 23 (2019), pp. 1174-1179

[31] 31

MK. Nicholas

Depression in people with pain: There is still work to do Commentary on ‘Understanding the link between depression and pain’

Scand J Pain, 2 (2011), pp. 45-46

[32] 32

MK. Nicholas

Understanding the link between depression and pain

Scand J Pain, 2 (2011), pp. 45-46

Neuroligins facilitate the development of bone cancer pain via regulating synaptic transmission: an experimental study

Xianqiao Xie, Yang Li, Shanchun Su, Xiaohui Li, Xueqin Xu, Yan Gao, Minjing Peng, Changbin Ke

Abstract

Background

Methods

Results

Conclusions

Keywords

References

Links

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