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Open Access 01-12-2020 | Nerve Stimulation | Research

Interferon-γ acutely augments inhibition of neocortical layer 5 pyramidal neurons

Authors: Gabriel M. S. Janach, Olivia Reetz, Noah Döhne, Konstantin Stadler, Sabine Grosser, Egor Byvaltcev, Anja U. Bräuer, Ulf Strauss

Published in: Journal of Neuroinflammation | Issue 1/2020

Abstract

Background

Interferon-γ (IFN-γ, a type II IFN) is present in the central nervous system (CNS) under various conditions. Evidence is emerging that, in addition to its immunological role, IFN-γ modulates neuronal morphology, function, and development in several brain regions. Previously, we have shown that raising levels of IFN-β (a type I IFN) lead to increased neuronal excitability of neocortical layer 5 pyramidal neurons. Because of shared non-canonical signaling pathways of both cytokines, we hypothesized a similar neocortical role of acutely applied IFN-γ.

Methods

We used semi-quantitative RT-PCR, immunoblotting, and immunohistochemistry to analyze neuronal expression of IFN-γ receptors and performed whole-cell patch-clamp recordings in layer 5 pyramidal neurons to investigate sub- and suprathreshold excitability, properties of hyperpolarization-activated cyclic nucleotide-gated current (I_h), and inhibitory neurotransmission under the influence of acutely applied IFN-γ.

Results

We show that IFN-γ receptors are present in the membrane of rat’s neocortical layer 5 pyramidal neurons. As expected from this and the putative overlap in IFN type I and II alternative signaling pathways, IFN-γ diminished I_h, mirroring the effect of type I IFNs, suggesting a likewise activation of protein kinase C (PKC). In contrast, IFN-γ did neither alter subthreshold nor suprathreshold neuronal excitability, pointing to augmented inhibitory transmission by IFN-γ. Indeed, IFN-γ increased electrically evoked inhibitory postsynaptic currents (IPSCs) on neocortical layer 5 pyramidal neurons. Furthermore, amplitudes of spontaneous IPSCs and miniature IPSCs were elevated by IFN-γ, whereas their frequency remained unchanged.

Conclusions

The expression of IFN-γ receptors on layer 5 neocortical pyramidal neurons together with the acute augmentation of inhibition in the neocortex by direct application of IFN-γ highlights an additional interaction between the CNS and immune system. Our results strengthen our understanding of the role of IFN-γ in neocortical neurotransmission and emphasize its impact beyond its immunological properties, particularly in the pathogenesis of neuropsychiatric disorders.

Owens T, Khorooshi R, Wlodarczyk A, Asgari N. Interferons in the central nervous system: a few instruments play many tunes. Glia. 2014;62:339–55.PubMedCrossRef

Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004;75:163–89.PubMedCrossRef

Monteiro S, Roque S, Marques F, Correia-Neves M, Cerqueira JJ. Brain interference: revisiting the role of IFNγ in the central nervous system. Prog Neurobiol. 2017;156:149–63.PubMedCrossRef

Traugott U, Lebon P. Interferon-gamma and Ia antigen are present on astrocytes in active chronic multiple sclerosis lesions. J Neurol Sci. 1988;84:257–64.PubMedCrossRef

Li HL, Kostulas N, Huang YM, Xiao BG, van der Meide P, Kostulas V, et al. IL-17 and IFN-gamma mRNA expression is increased in the brain and systemically after permanent middle cerebral artery occlusion in the rat. J Neuroimmunol. 2001;116:5–14.PubMedCrossRef

Lau LT, Yu AC. Astrocytes produce and release interleukin-1, interleukin-6, tumor necrosis factor alpha and interferon-gamma following traumatic and metabolic injury. J Neurotrauma. 2001;18:351–9.PubMedCrossRef

Heremans H, Billiau A, De Somer P. Interferon in experimental viral infections in mice: tissue interferon levels resulting from the virus infection and from exogenous interferon therapy. Infect Immun. 1980;30:513–22.PubMedPubMedCentral

Frei K, Leist TP, Meager A, Gallo P, Leppert D, Zinkernagel RM, et al. Production of B cell stimulatory factor-2 and interferon gamma in the central nervous system during viral meningitis and encephalitis. Evaluation in a murine model infection and in patients. J Exp Med. 1988;168:449–53.PubMedCrossRef

Reyes-Vázquez C, Prieto-Gómez B, Dafny N. Interferon modulates central nervous system function. Brain Res. 2012;1442:76–89.PubMedCrossRef

10.

Monteiro S, Ferreira FM, Pinto V, Roque S, Morais M, de Sá-Calçada D, et al. Absence of IFNγ promotes hippocampal plasticity and enhances cognitive performance. Transl Psychiatry. 2016;6:e707.PubMedPubMedCentralCrossRef

11.

Di Liberto G, Pantelyushin S, Kreutzfeldt M, Page N, Musardo S, Coras R, et al. Neurons under T cell attack coordinate phagocyte-mediated synaptic stripping. Cell. 2018;175:458–71 e19.PubMedCrossRef

12.

Sun L, Tian Z, Wang J. A direct cross-talk between interferon-gamma and sonic hedgehog signaling that leads to the proliferation of neuronal precursor cells. Brain Behav Immun. 2010;24:220–8.PubMedCrossRef

13.

Schmidt FM, Lichtblau N, Minkwitz J, Chittka T, Thormann J, Kirkby KC, et al. Cytokine levels in depressed and non-depressed subjects, and masking effects of obesity. J Psychiatr Res. 2014;55:29–34.PubMedCrossRef

14.

Arolt V, Rothermundt M, Wandinger KP, Kirchner H. Decreased in vitro production of interferon-gamma and interleukin-2 in whole blood of patients with schizophrenia during treatment. Mol Psychiatry. 2000;5:150–8.PubMedCrossRef

15.

Platanias LC. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol. 2005;5:375–86.PubMedCrossRef

16.

Boehm U, Klamp T, Groot M, Howard JC. Cellular responses to interferon-gamma. Annu Rev Immunol. 1997;15:749–95.PubMedCrossRef

17.

Deb DK, Sassano A, Lekmine F, Majchrzak B, Verma A, Kambhampati S, et al. Activation of protein kinase C delta by IFN-gamma. J Immunol. 2003;171:267–73.PubMedCrossRef

18.

Srivastava KK, Batra S, Sassano A, Li Y, Majchrzak B, Kiyokawa H, et al. Engagement of protein kinase C-theta in interferon signaling in T-cells. J Biol Chem. 2004;279:29911–20.PubMedCrossRef

19.

Hald A, Andrés RM, Salskov-Iversen ML, Kjellerup RB, Iversen L, Johansen C. STAT1 expression and activation is increased in lesional psoriatic skin. Br J Dermatol. 2013;168:302–10.PubMedCrossRef

20.

Hadjilambreva G, Mix E, Rolfs A, Müller J, Strauss U. Neuromodulation by a cytokine: interferon-beta differentially augments neocortical neuronal activity and excitability. J Neurophysiol. 2005;93:843–52.PubMedCrossRef

21.

Reetz O, Stadler K, Strauss U. Protein kinase C activation mediates interferon-β-induced neuronal excitability changes in neocortical pyramidal neurons. J Neuroinflammation. 2014;11:185.PubMedPubMedCentralCrossRef

22.

Stadler K, Bierwirth C, Stoenica L, Battefeld A, Reetz O, Mix E, et al. Elevation in type I interferons inhibits HCN1 and slows cortical neuronal oscillations. Cereb Cortex. 2014;24:199–210 Oxford University Press.PubMedCrossRef

23.

Brask J, Kristensson K, Hill RH. Exposure to interferon-gamma during synaptogenesis increases inhibitory activity after a latent period in cultured rat hippocampal neurons. Eur J Neurosci. 2004;19:3193–201.PubMedCrossRef

24.

Mizuno T, Zhang G, Takeuchi H, Kawanokuchi J, Wang J, Sonobe Y, et al. Interferon-gamma directly induces neurotoxicity through a neuron specific, calcium-permeable complex of IFN-gamma receptor and AMPA GluR1 receptor. FASEB J. 2008;22:1797–806.PubMedCrossRef

25.

Vikman KS, Owe-Larsson B, Brask J, Kristensson KS, Hill RH. Interferon-gamma-induced changes in synaptic activity and AMPA receptor clustering in hippocampal cultures. Brain Res. 2001;896:18–29.PubMedCrossRef

26.

Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012;9:676–82.PubMedCrossRef

27.

Strauss U, Kole MH, Bräuer AUA, Pahnke J, Bajorat R, Rolfs A, et al. An impaired neocortical Ih is associated with enhanced excitability and absence epilepsy. Eur J Neurosci. 2004;19:3048–58.PubMedCrossRef

28.

Feng L, Zhao T, Kim J. neuTube 1.0: a new design for efficient neuron reconstruction software based on the SWC format. eNeuro. 2015;2. ENEURO.0049-14.2014.PubMedPubMedCentralCrossRef

29.

Robertson B, Kong G, Peng Z, Bentivoglio M, Kristensson K. Interferon-gamma-responsive neuronal sites in the normal rat brain: receptor protein distribution and cell activation revealed by Fos induction. Brain Res Bull. 2000;52:61–74.PubMedCrossRef

30.

Aguet M, Dembić Z, Merlin G. Molecular cloning and expression of the human interferon-gamma receptor. Cell. 1988;55:273–80.PubMedCrossRef

31.

Gough DJ, Messina NL, Hii L, Gould JA, Sabapathy K, Robertson APS, et al. Functional crosstalk between type I and II interferon through the regulated expression of STAT1. PLoS Biol. 2010;8:e1000361.PubMedPubMedCentralCrossRef

32.

Fellous JM, Rudolph M, Destexhe A, Sejnowski TJ. Synaptic background noise controls the input/output characteristics of single cells in an in vitro model of in vivo activity. Neuroscience. 2003;122:811–29.PubMedCrossRef

33.

Chance FS, Abbott LF, Reyes AD. Gain modulation from background synaptic input. Neuron. 2002;35:773–82.PubMedCrossRef

34.

Chen X, Shu S, Schwartz LC, Sun C, Kapur J, Bayliss DA. Homeostatic regulation of synaptic excitability: tonic GABA(A) receptor currents replace I(h) in cortical pyramidal neurons of HCN1 knock-out mice. J Neurosci. 2010;30:2611–22.PubMedPubMedCentralCrossRef

35.

Micheva KD, Beaulieu C. Development and plasticity of the inhibitory neocortical circuitry with an emphasis on the rodent barrel field cortex: a review. Can J Physiol Pharmacol. 1997;75:470–8.PubMedCrossRef

36.

Filiano AJ, Xu Y, Tustison NJ, Marsh RL, Baker W, Smirnov I, et al. Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour. Nature. 2016;535:425–9 Nature Publishing Group.PubMedPubMedCentralCrossRef

37.

Flood L, Korol SV, Ekselius L, Birnir B, Jin Z. Interferon-γ potentiates GABAA receptor-mediated inhibitory currents in rat hippocampal CA1 pyramidal neurons. J Neuroimmunol. 2019;337:577050.PubMedCrossRef

38.

Flores CE, Nikonenko I, Mendez P, Fritschy J-M, Tyagarajan SK, Muller D. Activity-dependent inhibitory synapse remodeling through gephyrin phosphorylation. Proc Natl Acad Sci U S A. 2015;112:E65–72 National Acad Sciences.PubMedCrossRef

39.

Vikman KS, Duggan AW, Siddall PJ. Interferon-gamma induced disruption of GABAergic inhibition in the spinal dorsal horn in vivo. Pain. 2007;133:18–28.PubMedCrossRef

40.

Zhu PJ, Huang W, Kalikulov D, Yoo JW, Placzek AN, Stoica L, et al. Suppression of PKR promotes network excitability and enhanced cognition by interferon-γ-mediated disinhibition. Cell. 2011;147:1384–96.PubMedPubMedCentralCrossRef

41.

Müller M, Fontana A, Zbinden G, Gähwiler BH. Effects of interferons and hydrogen peroxide on CA3 pyramidal cells in rat hippocampal slice cultures. Brain Res. 1993;619:157–62.PubMedCrossRef

42.

Vezzani A, Viviani B. Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability. Neuropharmacology. 2015;96:70–82.PubMedCrossRef

43.

Beattie EC, Stellwagen D, Morishita W, Bresnahan JC, Ha BK, von Zastrow M, et al. Control of synaptic strength by glial TNFalpha. Science. 2002;295:2282–5.PubMedCrossRef

44.

Imaizumi T, Matsumiya T, Fujimoto K, Okamoto K, Cui X, Ohtaki U, et al. Interferon-gamma stimulates the expression of CX3CL1/fractalkine in cultured human endothelial cells. Tohoku J Exp Med. Tohoku University Medical Press. 2000;192:127–39.PubMedCrossRef

45.

Yoshida H, Imaizumi T, Fujimoto K, Matsuo N, Kimura K, Cui X, et al. Synergistic stimulation, by tumor necrosis factor-alpha and interferon-gamma, of fractalkine expression in human astrocytes. Neurosci Lett. 2001;303:132–6.PubMedCrossRef

46.

Heinisch S, Kirby LG. Fractalkine/CX3CL1 enhances GABA synaptic activity at serotonin neurons in the rat dorsal raphe nucleus. Neuroscience. 2009;164:1210–23.PubMedCrossRef

47.

Ta T-T, Dikmen HO, Schilling S, Chausse B, Lewen A, Hollnagel J-O, et al. Priming of microglia with IFN-γ slows neuronal gamma oscillations in situ. Proc Natl Acad Sci U S A. 2019;116(10):4637–42.CrossRef

48.

Bertot C, Groc L, Avignone E. Role of CX3CR1 signaling on the maturation of GABAergic transmission and neuronal network activity in the neonate hippocampus. Neuroscience. 2019;406:186–201.PubMedCrossRef

49.

Ladogana A, Bouzamondo E, Pocchiari M, Tsiang H. Modification of tritiated gamma-amino-n-butyric acid transport in rabies virus-infected primary cortical cultures. J Gen Virol. 1994;75(Pt 3):623–7.PubMedCrossRef

50.

Brask J, Owe-Larsson B, Hill RH, Kristensson K. Changes in calcium currents and GABAergic spontaneous activity in cultured rat hippocampal neurons after a neurotropic influenza A virus infection. Brain Res Bull. 2001;55:421–9.PubMedCrossRef

51.

Schmidt FM, Schröder T, Kirkby KC, Sander C, Suslow T, Holdt LM, et al. Pro- and anti-inflammatory cytokines, but not CRP, are inversely correlated with severity and symptoms of major depression. Psychiatry Res. 2016;239:85–91.PubMedCrossRef

52.

Mandolesi G, Bullitta S, Fresegna D, Gentile A, De Vito F, Dolcetti E, et al. Interferon-γ causes mood abnormalities by altering cannabinoid CB1 receptor function in the mouse striatum. Neurobiol Dis. 2017;108:45–53.PubMedCrossRef

53.

Getts DR, Matsumoto I, Müller M, Getts MT, Radford J, Shrestha B, et al. Role of IFN-gamma in an experimental murine model of West Nile virus-induced seizures. J Neurochem. 2007;103:1019–30.PubMedCrossRef

Title: Interferon-γ acutely augments inhibition of neocortical layer 5 pyramidal neurons
Authors: Gabriel M. S. Janach
Olivia Reetz
Noah Döhne
Konstantin Stadler
Sabine Grosser
Egor Byvaltcev
Anja U. Bräuer
Ulf Strauss
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Nerve Stimulation
Interferon
Published in: Journal of Neuroinflammation / Issue 1/2020
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-020-1722-y

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Springer Medicine

Interferon-γ acutely augments inhibition of neocortical layer 5 pyramidal neurons

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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