Glutamatergic CYLD Deletion Leads to Aberrant Excitatory Activity in the Basolateral Amygdala: Association with Enhanced Cued Fear Expression

Overview

Journal Neural Regen Res

Date 2024 Dec 23

PMID 39715097

Authors

Huidong Li

Faqin Li

Zhaoyi Chen

Erwen Wu

Xiaoxi Dai

Danni Li

Haojie An

Shiyi Zeng

Chunyan Wang

Li Yang

Cheng Long

Affiliations

Soon will be listed here.

Abstract

JOURNAL/nrgr/04.03/01300535-202511000-00029/figure1/v/2024-12-20T164640Z/r/image-tiff Neuronal activity, synaptic transmission, and molecular changes in the basolateral amygdala play critical roles in fear memory. Cylindromatosis (CYLD) is a deubiquitinase that negatively regulates the nuclear factor kappa-B pathway. CYLD is well studied in non-neuronal cells, yet under-investigated in the brain, where it is highly expressed. Emerging studies have shown involvement of CYLD in the remodeling of glutamatergic synapses, neuroinflammation, fear memory, and anxiety- and autism-like behaviors. However, the precise role of CYLD in glutamatergic neurons is largely unknown. Here, we first proposed involvement of CYLD in cued fear expression. We next constructed transgenic model mice with specific deletion of Cyld from glutamatergic neurons. Our results show that glutamatergic CYLD deficiency exaggerated the expression of cued fear in only male mice. Further, loss of CYLD in glutamatergic neurons resulted in enhanced neuronal activation, impaired excitatory synaptic transmission, and altered levels of glutamate receptors accompanied by over-activation of microglia in the basolateral amygdala of male mice. Altogether, our study suggests a critical role of glutamatergic CYLD in maintaining normal neuronal, synaptic, and microglial activation. This may contribute, at least in part, to cued fear expression.

Citing Articles

Role of CYLD in brain physiology and pathology.

Nardi L, Bicker F, Maier J, Waisman A, Schmeisser M J Mol Med (Berl). 2025; 103(3):255-263.

PMID: 39945824 PMC: 11880164. DOI: 10.1007/s00109-025-02521-4.

References

Maroun M . Medial prefrontal cortex: multiple roles in fear and extinction. Neuroscientist. 2012; 19(4):370-83. DOI: 10.1177/1073858412464527. View

Hrdinka M, Fiil B, Zucca M, Leske D, Bagola K, Yabal M . CYLD Limits Lys63- and Met1-Linked Ubiquitin at Receptor Complexes to Regulate Innate Immune Signaling. Cell Rep. 2016; 14(12):2846-58. PMC: 4819907. DOI: 10.1016/j.celrep.2016.02.062. View

Zhu H, Guan A, Liu J, Peng L, Zhang Z, Wang S . Noteworthy perspectives on microglia in neuropsychiatric disorders. J Neuroinflammation. 2023; 20(1):223. PMC: 10548593. DOI: 10.1186/s12974-023-02901-y. View

Roemers P, Hulst Y, van Heijningen S, van Dijk G, van Heuvelen M, De Deyn P . Inducing Physical Inactivity in Mice: Preventing Climbing and Reducing Cage Size Negatively Affect Physical Fitness and Body Composition. Front Behav Neurosci. 2019; 13:221. PMC: 6797814. DOI: 10.3389/fnbeh.2019.00221. View

Shabab T, Khanabdali R, Zorofchian Moghadamtousi S, Kadir H, Mohan G . Neuroinflammation pathways: a general review. Int J Neurosci. 2016; 127(7):624-633. DOI: 10.1080/00207454.2016.1212854. View

Guo Y, Lu Y, Zheng Y, Chen X, Dong J, Yuan R . Ubiquitin C-Terminal Hydrolase L1 (UCH-L1) Promotes Hippocampus-Dependent Memory via Its Deubiquitinating Effect on TrkB. J Neurosci. 2017; 37(25):5978-5995. PMC: 6596500. DOI: 10.1523/JNEUROSCI.3148-16.2017. View

Zajicek A, Yao W . Remodeling without destruction: non-proteolytic ubiquitin chains in neural function and brain disorders. Mol Psychiatry. 2020; 26(1):247-264. PMC: 9229342. DOI: 10.1038/s41380-020-0849-7. View

Baldi E, Bucherelli C . Brain sites involved in fear memory reconsolidation and extinction of rodents. Neurosci Biobehav Rev. 2015; 53:160-90. DOI: 10.1016/j.neubiorev.2015.04.003. View

Marek R, Strobel C, Bredy T, Sah P . The amygdala and medial prefrontal cortex: partners in the fear circuit. J Physiol. 2013; 591(10):2381-91. PMC: 3678031. DOI: 10.1113/jphysiol.2012.248575. View

10.

Reiley W, Zhang M, Jin W, Losiewicz M, Donohue K, Norbury C . Regulation of T cell development by the deubiquitinating enzyme CYLD. Nat Immunol. 2006; 7(4):411-7. DOI: 10.1038/ni1315. View

11.

Sharp B . Basolateral amygdala and stress-induced hyperexcitability affect motivated behaviors and addiction. Transl Psychiatry. 2017; 7(8):e1194. PMC: 5611728. DOI: 10.1038/tp.2017.161. View

12.

Yiu A, Mercaldo V, Yan C, Richards B, Rashid A, Hsiang H . Neurons are recruited to a memory trace based on relative neuronal excitability immediately before training. Neuron. 2014; 83(3):722-35. DOI: 10.1016/j.neuron.2014.07.017. View

13.

Feng X, Hu H, Chen J, Long C, Yang L, Wang L . Acute neuroinflammation increases excitability of prefrontal parvalbumin interneurons and their functional recruitment during novel object recognition. Brain Behav Immun. 2021; 98:48-58. DOI: 10.1016/j.bbi.2021.08.216. View

14.

Chaaya N, Battle A, Johnson L . An update on contextual fear memory mechanisms: Transition between Amygdala and Hippocampus. Neurosci Biobehav Rev. 2018; 92:43-54. DOI: 10.1016/j.neubiorev.2018.05.013. View

15.

Bjorefeldt A, Andreasson U, Daborg J, Riebe I, Wasling P, Zetterberg H . Human cerebrospinal fluid increases the excitability of pyramidal neurons in the in vitro brain slice. J Physiol. 2015; 593(1):231-43. PMC: 4293065. DOI: 10.1113/jphysiol.2014.284711. View

16.

Chen S, Liu K, Tan S, Chen X, Li H, Li J . Deubiquitinase CYLD regulates excitatory synaptic transmission and short-term plasticity in the hippocampus. Brain Res. 2023; 1806:148313. DOI: 10.1016/j.brainres.2023.148313. View

17.

Massoumi R . Ubiquitin chain cleavage: CYLD at work. Trends Biochem Sci. 2010; 35(7):392-9. DOI: 10.1016/j.tibs.2010.02.007. View

18.

Jolly L, Kumar R, Penzes P, Piper M, Gecz J . The DUB Club: Deubiquitinating Enzymes and Neurodevelopmental Disorders. Biol Psychiatry. 2022; 92(8):614-625. PMC: 10084722. DOI: 10.1016/j.biopsych.2022.03.022. View

19.

Kovalenko A, Chable-Bessia C, Cantarella G, Israel A, Wallach D, Courtois G . The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature. 2003; 424(6950):801-5. DOI: 10.1038/nature01802. View

20.

Lee D, Lee J, Hong D, Lee E, Park S, Lee M . Neuroinflammation in Post-Traumatic Stress Disorder. Biomedicines. 2022; 10(5). PMC: 9138406. DOI: 10.3390/biomedicines10050953. View