Skip to main content

Advertisement

Log in

PSD-93 up-regulates the synaptic activity of corticotropin-releasing hormone neurons in the paraventricular nucleus in depression

Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Since the discovery of ketamine anti-depressant effects in last decade, it has effectively revitalized interest in investigating excitatory synapses hypothesis in the pathogenesis of depression. In the present study, we aimed to reveal the excitatory synaptic regulation of corticotropin-releasing hormone (CRH) neuron in the hypothalamus, which is the driving force in hypothalamic–pituitary–adrenal (HPA) axis regulation. This study constitutes the first observation of an increased density of PSD-93-CRH co-localized neurons in the hypothalamic paraventricular nucleus (PVN) of patients with major depression. PSD-93 overexpression in CRH neurons in the PVN induced depression-like behaviors in mice, accompanied by increased serum corticosterone level. PSD-93 knockdown relieved the depression-like phenotypes in a lipopolysaccharide (LPS)-induced depression model. Electrophysiological data showed that PSD-93 overexpression increased CRH neurons synaptic activity, while PSD-93 knockdown decreased CRH neurons synaptic activity. Furthermore, we found that LPS induced increased the release of glutamate from microglia to CRH neurons resulted in depression-like behaviors using fiber photometry recordings. Together, these results show that PSD-93 is involved in the pathogenesis of depression via increasing the synaptic activity of CRH neurons in the PVN, leading to the hyperactivity of the HPA axis that underlies depression-like behaviors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Amionff M, Boller F, Swaab D (2003) Handbook of clinical neurology, Vol. 79. The human hypothalamus: basic and clinical aspects Part I. Elsevier, Amsterdam

  2. Banki CM, Bissette G, Arato M, O’Connor L, Nemeroff CB (1987) CSF corticotropin-releasing factor-like immunoreactivity in depression and schizophrenia. Am J Psychiatry 144:873–877. https://doi.org/10.1176/ajp.144.7.873

    Article  CAS  PubMed  Google Scholar 

  3. Bao AM, Swaab DF (2019) The human hypothalamus in mood disorders: the HPA axis in the center. IBRO Rep 6:45–53. https://doi.org/10.1016/j.ibror.2018.11.008

    Article  PubMed  Google Scholar 

  4. Bao AM, Hestiantoro A, Van Someren EJ, Swaab DF, Zhou JN (2005) Colocalization of corticotropin-releasing hormone and oestrogen receptor-alpha in the paraventricular nucleus of the hypothalamus in mood disorders. Brain 128:1301–1313. https://doi.org/10.1093/brain/awh448

    Article  PubMed  Google Scholar 

  5. Barger SW, Basile AS (2001) Activation of microglia by secreted amyloid precursor protein evokes release of glutamate by cystine exchange and attenuates synaptic function. J Neurochem 76:846–854

    Article  CAS  Google Scholar 

  6. Barger SW, Goodwin ME, Porter MM, Beggs ML (2007) Glutamate release from activated microglia requires the oxidative burst and lipid peroxidation. J Neurochem 101:1205–1213. https://doi.org/10.1111/j.1471-4159.2007.04487.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Beliveau BJ, Kishi JY, Nir G, Sasaki HM, Saka SK, Nguyen SC et al (2018) OligoMiner provides a rapid, flexible environment for the design of genome-scale oligonucleotide in situ hybridization probes. Proc Natl Acad Sci 115:E2183–E2192

    Article  CAS  Google Scholar 

  8. Caceres A, Binder L, Payne M, Bender P, Rebhun L, Steward O (1984) Differential subcellular localization of tubulin and the microtubule-associated protein MAP2 in brain tissue as revealed by immunocytochemistry with monoclonal hybridoma antibodies. J Neurosci 4:394–410

    Article  CAS  Google Scholar 

  9. Cai Z, Hussain MD, Yan LJ (2014) Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer’s disease. Int J Neurosci 124:307–321. https://doi.org/10.3109/00207454.2013.833510

    Article  CAS  PubMed  Google Scholar 

  10. Carlisle HJ, Fink AE, Grant SG, O’Dell TJ (2008) Opposing effects of PSD-93 and PSD-95 on long-term potentiation and spike timing-dependent plasticity. J Physiol 586:5885–5900. https://doi.org/10.1113/jphysiol.2008.163469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cai L, Yan XB, Chen XN, Meng QY, Zhou JN (2010) Chronic all-trans retinoic acid administration induced hyperactivity of HPA axis and behavioral changes in young rats. European Neuropsychopharmacol 20(12):839–847. https://doi.org/10.1016/j.euroneuro.2010.06.019

    Article  CAS  Google Scholar 

  12. Chen X-N, Meng Q-Y, Bao A-M, Swaab DF, Wang G-H, Zhou J-N (2009) The involvement of retinoic acid receptor-α in corticotropin-releasing hormone gene expression and affective disorders. Biol Psychiat 66:832–839. https://doi.org/10.1016/j.biopsych.2009.05.031

    Article  CAS  PubMed  Google Scholar 

  13. Chen P, Lou S, Huang ZH, Wang Z, Shan QH, Wang Y et al (2020) Prefrontal cortex corticotropin-releasing factor neurons control behavioral style selection under challenging situations. Neuron 106(301–315):e307. https://doi.org/10.1016/j.neuron.2020.01.033

    Article  CAS  Google Scholar 

  14. Choi HMT, Schwarzkopf M, Fornace ME, Acharya A, Artavanis G, Stegmaier J et al (2018) Third-generation in situ hybridization chain reaction: multiplexed, quantitative, sensitive, versatile, robust. Development. https://doi.org/10.1242/dev.165753

    Article  PubMed  PubMed Central  Google Scholar 

  15. Cserep C, Posfai B, Denes A (2021) Shaping neuronal fate: functional heterogeneity of direct microglia-neuron interactions. Neuron 109:222–240. https://doi.org/10.1016/j.neuron.2020.11.007

    Article  CAS  PubMed  Google Scholar 

  16. Duman RS, Aghajanian GK, Sanacora G, Krysta JH (2016) Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med 22:238–249. https://doi.org/10.1038/nm.4050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Duric V, Banasr M, Stockmeier CA, Simen AA, Newton SS, Overholser JC et al (2013) Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects. Int J Neuropsychopharmacol 16:69–82. https://doi.org/10.1017/S1461145712000016

    Article  CAS  PubMed  Google Scholar 

  18. Elias GM, Funke L, Stein V, Grant SG, Bredt DS, Nicoll RA (2006) Synapse-specific and developmentally regulated targeting of AMPA receptors by a family of MAGUK scaffolding proteins. Neuron 52:307–320. https://doi.org/10.1016/j.neuron.2006.09.012

    Article  CAS  PubMed  Google Scholar 

  19. Frenois F, Moreau M, O’Connor J, Lawson M, Micon C, Lestage J et al (2007) Lipopolysaccharide induces delayed FosB/DeltaFosB immunostaining within the mouse extended amygdala, hippocampus and hypothalamus, that parallel the expression of depressive-like behavior. Psychoneuroendocrinology 32:516–531. https://doi.org/10.1016/j.psyneuen.2007.03.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fuchs E, Czeh B, Flügge G (2004) Examining novel concepts of the pathophysiology of depression in the chronic psychosocial stress paradigm in tree shrews. Behav Pharmacol 15:315–325

    Article  CAS  Google Scholar 

  21. Futai K, Kim MJ, Hashikawa T, Scheiffele P, Sheng M, Hayashi Y (2007) Retrograde modulation of presynaptic release probability through signaling mediated by PSD-95-neuroligin. Nat Neurosci 10:186–195. https://doi.org/10.1038/nn1837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gao TH, Ni RJ, Liu S, Tian Y, Wei J, Zhao L et al (2021) Chronic lithium exposure attenuates ketamine-induced mania-like behavior and c-Fos expression in the forebrain of mice. Pharmacol Biochem Behav 202:173108. https://doi.org/10.1016/j.pbb.2021.173108

    Article  CAS  PubMed  Google Scholar 

  23. Goh JJL, Chou N, Seow WY, Ha N, Cheng CPP, Chang YC et al (2020) Highly specific multiplexed RNA imaging in tissues with split-FISH. Nat Methods 17:689–693. https://doi.org/10.1038/s41592-020-0858-0

    Article  CAS  PubMed  Google Scholar 

  24. Grieder TE, Herman MA, Contet C, Tan LA, Vargas-Perez H, Cohen A et al (2014) VTA CRF neurons mediate the aversive effects of nicotine withdrawal and promote intake escalation. Nat Neurosci 17:1751–1758. https://doi.org/10.1038/nn.3872

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hart BL (1988) Biological basis of the behavior of sick animals. Neurosci Biobehav Rev 12:123–137

    Article  CAS  Google Scholar 

  26. Hashimoto K (2019) Rapid-acting anti-depressant ketamine, its metabolites and other candidates: a historical overview and future perspective. Psychiatry Clin Neurosci 73:613–627. https://doi.org/10.1111/pcn.12902

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Howard DM, Adams MJ, Shirali M, Clarke TK, Marioni RE, Davies G et al (2018) Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways (2018). Nat Commun. https://doi.org/10.1038/s41467-018-05310-5

    Article  PubMed  PubMed Central  Google Scholar 

  28. Hu P, Liu J, Zhao J, Qi XR, Qi CC, Lucassen PJ et al (2013) All-trans retinoic acid-induced hypothalamus-pituitary-adrenal hyperactivity involves glucocorticoid receptor dysregulation. Transl Psychiatry 3:e336. https://doi.org/10.1038/tp.2013.98

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Keck ME, Holsboer F (2001) Hyperactivity of CRH neuronal circuits as a target for therapeutic interventions in affective disorders. Peptides 22:835–844. https://doi.org/10.1016/S0196-9781(01)00398-9

    Article  CAS  PubMed  Google Scholar 

  30. Keller J, Gomez R, Williams G, Lembke A, Lazzeroni L, Murphy GM Jr et al (2017) HPA axis in major depression: cortisol, clinical symptomatology and genetic variation predict cognition. Mol Psychiatry 22:527–536. https://doi.org/10.1038/mp.2016.120

    Article  CAS  PubMed  Google Scholar 

  31. Kim E, Cho KO, Rothschild A, Sheng M (1996) Heteromultimerization and NMDA receptor-clustering activity of Chapsyn-110, a member of the PSD-95 family of proteins. Neuron 17:103–113

    Article  CAS  Google Scholar 

  32. Kornau H-C, Schenker LT, Kennedy MB, Seeburg PH (1995) Domain interaction between NMDA receptor subunits and the post-synaptic density protein PSD-95. Science 269:1737–1740

    Article  CAS  Google Scholar 

  33. Korosi A, Shanabrough M, McClelland S, Liu ZW, Borok E, Gao XB et al (2010) Early-life experience reduces excitation to stress-responsive hypothalamic neurons and reprograms the expression of corticotropin-releasing hormone. J Neurosci 30:703–713. https://doi.org/10.1523/JNEUROSCI.4214-09.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kruger JM, Favaro PD, Liu M, Kitlinska A, Huang X, Raabe M et al (2013) Differential roles of postsynaptic density-93 isoforms in regulating synaptic transmission. J Neurosci 33:15504–15517. https://doi.org/10.1523/JNEUROSCI.0019-12.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Krystal JH, Abdallah CG, Sanacora G, Charney DS, Duman RS (2019) Ketamine: a paradigm shift for depression research and treatment. Neuron 101:774–778. https://doi.org/10.1016/j.neuron.2019.02.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Levy BH, Tasker JG (2012) Synaptic regulation of the hypothalamic–pituitary–adrenal axis and its modulation by glucocorticoids and stress. Front Cell Neurosci. https://doi.org/10.3389/fncel.2012.00024

    Article  PubMed  PubMed Central  Google Scholar 

  37. Lin H-C, Wan F-J, Kang B-H, Wu C-C, Tseng C-J (1999) Systemic administration of lipopolysaccharide induces release of nitric oxide and glutamate and c-fos expression in the nucleus tractus solitarii of rats. Hypertension 33:1218–1224

    Article  CAS  Google Scholar 

  38. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262

    Article  CAS  PubMed  Google Scholar 

  39. Mai J, Assheuer J, Paxinos G (2004) Atlas of the human brain. Elsevier Academic Press, Amsterdam

    Google Scholar 

  40. Marvin JS, Scholl B, Wilson DE, Podgorski K, Kazemipour A, Muller JA et al (2018) Stability, affinity, and chromatic variants of the glutamate sensor iGluSnFR. Nat Methods 15:936–939. https://doi.org/10.1038/s41592-018-0171-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Mayer SE, Lopez-Duran NL, Sen S, Abelson JL (2018) Chronic stress, hair cortisol and depression: a prospective and longitudinal study of medical internship. Psychoneuroendocrinology 92:57–65. https://doi.org/10.1016/j.psyneuen.2018.03.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. McCullumsmith RE, Kristiansen LV, Beneyto M, Scarr E, Dean B, Meador-Woodruff JH (2007) Decreased NR1, NR2A, and SAP102 transcript expression in the hippocampus in bipolar disorder. Brain Res 1127:108–118. https://doi.org/10.1016/j.brainres.2006.09.011

    Article  CAS  PubMed  Google Scholar 

  43. McGovern DJ, Polter AM, Root DH (2021) Neurochemical signaling of reward and aversion to ventral tegmental area glutamate neurons. J Neurosci 41:5471–5486. https://doi.org/10.1523/JNEUROSCI.1419-20.2021

    Article  CAS  PubMed  Google Scholar 

  44. Mello BS, Monte AS, McIntyre RS, Soczynska JK, Custodio CS, Cordeiro RC et al (2013) Effects of doxycycline on depressive-like behavior in mice after lipopolysaccharide (LPS) administration. J Psychiatr Res 47:1521–1529. https://doi.org/10.1016/j.jpsychires.2013.06.008

    Article  PubMed  Google Scholar 

  45. Meng FT, Ni RJ, Zhang Z, Zhao J, Liu YJ, Zhou JN (2011) Inhibition of oestrogen biosynthesis induces mild anxiety in C57BL/6J ovariectomized female mice. Neurosci Bull 27:241–250. https://doi.org/10.1007/s12264-011-1014-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Moda-Sava RN, Murdock MH, Parekh PK, Fetcho RN, Huang BS, Huynh TN et al (2019) Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science. https://doi.org/10.1126/science.aat8078

    Article  PubMed  PubMed Central  Google Scholar 

  47. Murugan M, Ling E-A, Kaur C (2013) Glutamate and microglia. CNS Neurol Disord Drug Targets (Former Curr Drug Targets CNS Neurol Disord) 12:773–784

    Article  CAS  Google Scholar 

  48. Nemeroff CB, Widerlov E, Bissette G, Walleus H, Karlsson I, Eklund K et al (1984) Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 226:1342–1344. https://doi.org/10.1126/science.6334362

    Article  CAS  PubMed  Google Scholar 

  49. Ni RJ, Shu YM, Wang J, Yin JC, Xu L, Zhou JN (2014) Distribution of vasopressin, oxytocin and vasoactive intestinal polypeptide in the hypothalamus and extrahypothalamic regions of tree shrews. Neuroscience 265:124–136. https://doi.org/10.1016/j.neuroscience.2014.01.034

    Article  CAS  PubMed  Google Scholar 

  50. Niethammer M, Kim E, Sheng M (1996) Interaction between the C terminus of NMDA receptor subunits and multiple members of the PSD-95 family of membrane-associated guanylate kinases. J Neurosci 16:2157–2163

    Article  CAS  Google Scholar 

  51. Nishino S, Mignot E, Benson KL, Zarcone VP Jr (1998) Cerebrospinal fluid prostaglandins and corticotropin releasing factor in schizophrenics and controls: relationship to sleep architecture. Psychiatry Res 78:141–150. https://doi.org/10.1016/s0165-1781(98)00012-2

    Article  CAS  PubMed  Google Scholar 

  52. O’Connor JC, Lawson MA, Andre C, Moreau M, Lestage J, Castanon N et al (2009) Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol Psychiatry 14:511–522. https://doi.org/10.1038/sj.mp.4002148

    Article  CAS  PubMed  Google Scholar 

  53. Ohgi Y, Futamura T, Kikuchi T, Hashimoto K (2013) Effects of antidepressants on alternations in serum cytokines and depressive-like behavior in mice after lipopolysaccharide administration. Pharmacol Biochem Behav 103:853–859. https://doi.org/10.1016/j.pbb.2012.12.003

    Article  CAS  PubMed  Google Scholar 

  54. Painsipp E, Kofer MJ, Sinner F, Holzer P (2011) Prolonged depression-like behavior caused by immune challenge: influence of mouse strain and social environment. PLoS ONE 6:e20719. https://doi.org/10.1371/journal.pone.0020719

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Pariante CM, Lightman SL (2008) The HPA axis in major depression: classical theories and new developments. Trends Neurosci 31:464–468. https://doi.org/10.1016/j.tins.2008.06.006

    Article  CAS  PubMed  Google Scholar 

  56. Park YG, Sohn CH, Chen R, McCue M, Yun DH, Drummond GT et al (2018) Protection of tissue physicochemical properties using polyfunctional crosslinkers. Nat Biotechnol. https://doi.org/10.1038/nbt.4281

    Article  PubMed  PubMed Central  Google Scholar 

  57. Patrizio M, Levi G (1994) Glutamate production by cultured microglia: differences between rat and mouse, enhancement by lipopolysaccharide and lack effect of HIV coat protein gp120 and depolarizing agents. Neurosci Lett 178:184–189. https://doi.org/10.1016/0304-3940(94)90755-2

    Article  CAS  PubMed  Google Scholar 

  58. Peng WH, Lo KL, Lee YH, Hung TH, Lin YC (2007) Berberine produces antidepressant-like effects in the forced swim test and in the tail suspension test in mice. Life Sci 81:933–938. https://doi.org/10.1016/j.lfs.2007.08.003

    Article  CAS  PubMed  Google Scholar 

  59. Piani D, Spranger M, Frei K, Schaffner A, Fontana A (1992) Macrophage-induced cytotoxicity of N-methyl-D-aspartate receptor positive neurons involves excitatory amino acids rather than reactive oxygen intermediates and cytokines. Eur J Immunol 22:2429–2436

    Article  CAS  Google Scholar 

  60. Porsolt RD, Bertin A, Jalfre M (1978) Behavioural despair in rats and mice: strain differences and the effects of imipramine. Eur J Pharmacol 51:291–294

    Article  CAS  Google Scholar 

  61. Qi CC, Zhang Z, Fang H, Liu J, Zhou N, Ge JF et al (2014) Antidepressant effects of abscisic acid mediated by the downregulation of corticotrophin-releasing hormone gene expression in rats. Int J Neuropsychopharmacol. https://doi.org/10.1093/ijnp/pyu006

    Article  PubMed  PubMed Central  Google Scholar 

  62. Qin XY, Fang H, Shan QH, Qi CC, Zhou JN (2020) All-trans retinoic acid-induced abnormal hippocampal expression of synaptic genes SynDIG1 and DLG2 is correlated with anxiety or depression-like behavior in mice. Int J Mol Sci. https://doi.org/10.3390/ijms21082677

    Article  PubMed  PubMed Central  Google Scholar 

  63. Raadsheer FC, Hoogendijk WJG, Stam FC, Tilders FJH, Swaab DF (1994) Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed-patients. Neuroendocrinology 60:436–444. https://doi.org/10.1159/000126778

    Article  CAS  PubMed  Google Scholar 

  64. Raadsheer FC, van Heerikhuize JJ, Lucassen PJ, Hoogendijk WJ, Tilders FJ, Swaab DF (1995) Corticotropin-releasing hormone mRNA levels in the paraventricular nucleus of patients with Alzheimer’s disease and depression. Am J Psychiatry 152:1372–1376. https://doi.org/10.1176/ajp.152.9.1372

    Article  CAS  PubMed  Google Scholar 

  65. Raone A, Cassanelli A, Scheggi S, Rauggi R, Danielli B, De Montis M (2007) Hypothalamus–pituitary–adrenal modifications consequent to chronic stress exposure in an experimental model of depression in rats. Neuroscience 146:1734–1742. https://doi.org/10.1016/j.neuroscience.2007.03.027

    Article  CAS  PubMed  Google Scholar 

  66. Schindler S, Schmidt L, Stroske M, Storch M, Anwander A, Trampel R et al (2019) Hypothalamus enlargement in mood disorders. Acta Psychiatr Scand 139:56–67. https://doi.org/10.1111/acps.12958

    Article  CAS  PubMed  Google Scholar 

  67. Schnell SA, Staines WA, Wessendorf MW (1999) Reduction of lipofuscin-like autofluorescence in fluorescently labeled tissue. J Histochem Cytochem 47:719–730. https://doi.org/10.1177/002215549904700601

    Article  CAS  PubMed  Google Scholar 

  68. Shen Y, Connor TJ, Nolan Y, Kelly JP, Leonard BE (1999) Differential effect of chronic antidepressant treatments on lipopolysaccharide-induced depressive-like behavioural symptoms in the rat. Life Sci 65:1773–1786. https://doi.org/10.1016/s0024-3205(99)00430-0

    Article  CAS  PubMed  Google Scholar 

  69. Shao W, Zhang S, Tang M, Zhang X, Zhou Z, Yin Y et al (2013) Suppression of neuroinflammation by astrocytic dopamine D2 receptors via αB-crystallin. Nature 494(7435):90–94. https://doi.org/10.1038/nature11748

  70. Siew LK, Love S, Dawbarn D, Wilcock GK, Allen SJ (2004) Measurement of pre- and post-synaptic proteins in cerebral cortex: effects of post-mortem delay. J Neurosci Methods 139:153–159. https://doi.org/10.1016/j.jneumeth.2004.04.020

    Article  CAS  PubMed  Google Scholar 

  71. Snyder JS, Soumier A, Brewer M, Pickel J, Cameron HA (2011) Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature 476:458–461. https://doi.org/10.1038/nature10287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology 85:367–370

    Article  CAS  Google Scholar 

  73. Stokes PE (1995) The potential role of excessive cortisol induced by HPA hyperfunction in the pathogenesis of depression. Eur Neuropsychopharmacol 5(Suppl):77–82. https://doi.org/10.1016/0924-977x(95)00039-r

    Article  CAS  PubMed  Google Scholar 

  74. Stokes PE, Sikes CR (1991) Hypothalamic-pituitary-adrenal axis in psychiatric disorders. Annu Rev Med 42:519–531. https://doi.org/10.1146/annurev.me.42.020191.002511

    Article  CAS  PubMed  Google Scholar 

  75. Strekalova T, Spanagel R, Bartsch D, Henn FA, Gass P (2004) Stress-induced anhedonia in mice is associated with deficits in forced swimming and exploration. Neuropsychopharmacology 29:2007–2017. https://doi.org/10.1038/sj.npp.1300532

    Article  PubMed  Google Scholar 

  76. Sulakhiya K, Kumar P, Jangra A, Dwivedi S, Hazarika NK, Baruah CC et al (2014) Honokiol abrogates lipopolysaccharide-induced depressive like behavior by impeding neuroinflammation and oxido-nitrosative stress in mice. Eur J Pharmacol 744:124–131. https://doi.org/10.1016/j.ejphar.2014.09.049

    Article  CAS  PubMed  Google Scholar 

  77. Sun Q, Turrigiano GG (2011) PSD-95 and PSD-93 play critical but distinct roles in synaptic scaling up and down. J Neurosci 31:6800–6808. https://doi.org/10.1523/JNEUROSCI.5616-10.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Takeuchi H, Jin S, Wang J, Zhang G, Kawanokuchi J, Kuno R et al (2006) Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J Biol Chem 281:21362–21368. https://doi.org/10.1074/jbc.M600504200

    Article  CAS  PubMed  Google Scholar 

  79. Thompson SM, Kallarackal AJ, Kvarta MD, Van Dyke AM, LeGates TA, Cai X (2015) An excitatory synapse hypothesis of depression. Trends Neurosci 38:279–294. https://doi.org/10.1016/j.tins.2015.03.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Trabzuni D, Ramasamy A, Imran S, Walker R, Smith C, Weale ME et al (2013) Widespread sex differences in gene expression and splicing in the adult human brain. Nat Commun 4:2771. https://doi.org/10.1038/ncomms3771

    Article  CAS  PubMed  Google Scholar 

  81. Tsai SF, Liu YW, Kuo YM (2019) Acute and long-term treadmill running differentially induce c-Fos expression in region- and time-dependent manners in mouse brain. Brain Struct Funct 224:2677–2689. https://doi.org/10.1007/s00429-019-01926-5

    Article  CAS  PubMed  Google Scholar 

  82. Walker AK, Budac DP, Bisulco S, Lee AW, Smith RA, Beenders B et al (2013) NMDA receptor blockade by ketamine abrogates lipopolysaccharide-induced depressive-like behavior in C57BL/6J mice. Neuropsychopharmacology 38:1609–1616. https://doi.org/10.1038/npp.2013.71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Wang SS, Kamphuis W, Huitinga I, Zhou JN, Swaab DF (2008) Gene expression analysis in the human hypothalamus in depression by laser microdissection and real-time PCR: the presence of multiple receptor imbalances. Mol Psychiatry 13(786–799):741. https://doi.org/10.1038/mp.2008.38

    Article  CAS  Google Scholar 

  84. Yang Y, Cui Y, Sang K, Dong Y, Ni Z, Ma S et al (2018) Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature 554:317

    Article  CAS  Google Scholar 

  85. Yirmiya R, Pollak Y, Barak O, Avitsur R, Ovadia H, Bette M et al (2001) Effects of antidepressant drugs on the behavioral and physiological responses to lipopolysaccharide (LPS) in rodents. Neuropsychopharmacology 24:531–544. https://doi.org/10.1016/S0893-133X(00)00226-8

    Article  CAS  PubMed  Google Scholar 

  86. Yu X, Jiang X, Zhang X, Chen Z, Xu L, Chen L et al (2016) The effects of fisetin on lipopolysaccharide-induced depressive-like behavior in mice. Metab Brain Dis 31:1011–1021. https://doi.org/10.1007/s11011-016-9839-5

    Article  CAS  PubMed  Google Scholar 

  87. Zhang M, Xu JT, Zhu X, Wang Z, Zhao X, Hua Z et al (2010) Postsynaptic density-93 deficiency protects cultured cortical neurons from N-methyl-D-aspartate receptor-triggered neurotoxicity. Neuroscience 166:1083–1090. https://doi.org/10.1016/j.neuroscience.2010.01.030

    Article  CAS  PubMed  Google Scholar 

  88. Zhang JY, Liu TH, He Y, Pan HQ, Zhang WH, Yin XP et al (2019) Chronic stress remodels synapses in an amygdala circuit-specific manner. Biol Psychiatry 85:189–201. https://doi.org/10.1016/j.biopsych.2018.06.019

    Article  CAS  PubMed  Google Scholar 

  89. Zhao J, Verwer RWH, Gao SF, Qi XR, Lucassen PJ, Kessels HW et al (2018) Prefrontal alterations in GABAergic and glutamatergic gene expression in relation to depression and suicide. J Psychiatr Res 102:261–274. https://doi.org/10.1016/j.jpsychires.2018.04.020

    Article  CAS  PubMed  Google Scholar 

  90. Zhou JJ, Gao Y, Zhang X, Kosten TA, Li DP (2018) Enhanced hypothalamic NMDA receptor activity contributes to hyperactivity of hpa axis in chronic stress in male rats. Endocrinology 159:1537–1546. https://doi.org/10.1210/en.2017-03176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zhu J, Shang Y, Zhang M (2016) Mechanistic basis of MAGUK-organized complexes in synaptic development and signalling. Nat Rev Neurosci 17:209–223. https://doi.org/10.1038/nrn.2016.18

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by National Natural Science Foundation of China (91732304 and 32030046), and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB02030001 and XDB32020200). We are grateful to the Netherlands Brain Bank for providing human brain material and clinical details. We thank Dr. Zhi Zhang (USTC) for providing the Cx3cr1-CreERT2 mice.

Author information

Authors and Affiliations

Authors

Contributions

J-NZ designed the studies. X-YQ and Q-HS performed most of the experiments and data analysis, and wrote the draft manuscript. HF, YW, and PC conducted some of the molecular experiments and behavioral experiments. Z-QX provided the plasmid. DS provided the human brain tissue and was involved in the revision of the manuscript. X-YQ and J-NZ wrote the paper.

Corresponding author

Correspondence to Jiang-Ning Zhou.

Ethics declarations

Conflict of interest

All authors claim that there are no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 28978 kb)

Supplementary file2 (MP4 32145 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qin, XY., Shan, QH., Fang, H. et al. PSD-93 up-regulates the synaptic activity of corticotropin-releasing hormone neurons in the paraventricular nucleus in depression. Acta Neuropathol 142, 1045–1064 (2021). https://doi.org/10.1007/s00401-021-02371-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-021-02371-7

Keywords

Navigation