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Social Isolation During Adolescence Induces Anxiety Behaviors and Enhances Firing Activity in BLA Pyramidal Neurons via mGluR5 Upregulation

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Abstract

Social isolation during the vulnerable period of adolescence contributes to the occurrence of psychiatric disorders and profoundly affects brain development and adult behavior. Although the impact of social isolation during adolescence on anxiety behaviors has been well studied, much less is known about the onset and underlying mechanisms of these behaviors. We observed that following 2 weeks, but not 1 week, of social isolation, adolescent mice exhibited anxiety behaviors. Strikingly, the mGluR5 protein levels in the amygdala increased concomitantly with anxiety behaviors, and both intraperitoneal administration and intra-basolateral amygdala (BLA) infusion of MPEP, a metabotropic glutamate receptor 5 antagonist, normalized anxiety behaviors. Furthermore, electrophysiological studies showed that 2 weeks of social isolation during adolescence facilitated pyramidal neuronal excitability in the BLA, which could be normalized by MPEP. Together, these results reveal a critical period in adolescence during which social isolation can induce anxiety behaviors and facilitate BLA pyramidal neuronal excitability, both of which are mediated by mGluR5, thus providing mechanistic insights into the onset of anxiety behaviors after social isolation during adolescence.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (81329003, 81671356, 31430032), the Program for Changjiang Scholars and Innovative Research Team in University (IRT_16R37), and Guangzhou Science and Technology Project (201707020027).

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  1. State Key Laboratory of Organ Failure Research, Key Laboratory of Psychiatric Disorders of Guangdong Province, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, 1023S Shatai Road, Guangzhou, 510515, China

    Song Lin, Xin Li, Yi-Hua Chen, Feng Gao, Hao Chen, Neng-Yuan Hu, Lang Huang, Zheng-Yi Luo, Ji-Hong Liu, Qiang-Long You, Ya-Nan Yin, Ze-Lin Li, Xiao-Wen Li, Zhuo-Jun Du, Jian-Ming Yang & Tian-Ming Gao

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Electronic Supplementary Material

Supplementary Figure 1

Effect of intra-BLA infusion of MPEP on anxiety-like behavior in normal mice. (a) Schematic of anxiety behaviors tested 30 min after MPEP administration. (b and c) In the EPM test, intra-BLA infusion of 2 and 20 μM MPEP had no effect on anxiety-like behaviors. Vehicle, n = 10; MPEP (2 μM), n = 9; MPEP (20 μM), n = 9; (d-f) In the OFT, intra-BLA infusion of 2 and 20 μM MPEP had no effect on anxiety-like behaviors. Vehicle, n = 10; MPEP (2 μM), n = 9; MPEP (20 μM), n = 9. NS, not significant; One-way ANOVA. Error bars indicate the SEM. (GIF 34 kb)

High resolution image (TIFF 940 kb)

Supplementary Figure 2

Two-week social isolation increased input resistance of pyramidal neurons in BLA. (a-c) RMP, spike threshold and input resistance in BLA pyramidal neurons from GH mice and 2w SI mice (n = 8, 3 GH mice; n = 7, 3 2w SI mice). *P < 0.05; NS, not significant; Student’s t test; Error bars indicate the SEM. (GIF 15 kb)

High resolution image (TIFF 357 kb)

Supplementary Figure 3

One-week social isolation did not affect the firing activity of pyramidal neurons in BLA. (a) Representative traces of AP evoked by injecting depolarizing current of 120 pA from GH mice and 1w SI mice. Scale bars: 200 ms, 40 pA. (b) Number of AP against injected current (n = 10, 3 GH mice; n = 11, 3 1w SI mice). (c) Representative traces of AP in response to depolarizing current ramps. (d) Cumulative AP latency for GH and 1w SI. (e) Average number of AP during current ramp application (n = 10, 3 GH mice; n = 11, 3 1w SI mice). (f-h) RMP, spike threshold and input resistance in BLA pyramidal neurons from GH mice and 1w SI mice (n = 10, 3 GH mice; n = 11, 3 1w SI mice). NS, not significant; Two-way ANOVA test for (b, d); Student’s t tests for (e-h). Error bars indicate the SEM. (GIF 33 kb)

High resolution image (TIFF 1189 kb)

Supplementary Figure 4

MPEP normalized the change of input resistance after two-week social isolation during adolescence. (a-c) spike threshold, RMP and input resistance in BLA pyramidal neurons from GH mice and 2w SI + MPEP mice (n = 10 per group from 4 mice). NS, not significant; Student’s t test; Error bars indicate the SEM. (GIF 17 kb)

High resolution image (TIFF 349 kb)

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Lin, S., Li, X., Chen, YH. et al. Social Isolation During Adolescence Induces Anxiety Behaviors and Enhances Firing Activity in BLA Pyramidal Neurons via mGluR5 Upregulation. Mol Neurobiol 55, 5310–5320 (2018). https://doi.org/10.1007/s12035-017-0766-1

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