Abstract
Neuroinflammation is consistently found in many neurological disorders, but whether or not the inflammatory response independently affects neuronal network properties is poorly understood. Here, we report that intracerebroventricular injection of the prototypical inflammatory molecule lipopolysaccharide (LPS) in rats triggered a strong and long-lasting inflammatory response in hippocampal microglia associated with a concomitant upregulation of Toll-like receptor (TLR4) in pyramidal and hilar neurons. This, in turn, was associated with a significant reduction of the dendritic hyperpolarization-activated cyclic AMP-gated channel type 1 (HCN1) protein level while Kv4.2 channels were unaltered as assessed by western blot. Immunohistochemistry confirmed the HCN1 decrease in CA1 pyramidal neurons and showed that these changes were associated with a reduction of TRIP8b, an auxiliary subunit for HCN channels implicated in channel subcellular localization and trafficking. At the physiological level, this effect translated into a 50% decrease in HCN1-mediated currents (Ih) measured in the distal dendrites of hippocampal CA1 pyramidal cells. At the functional level, the band-pass-filtering properties of dendrites in the theta frequency range (4–12 Hz) and their temporal summation properties were compromised. We conclude that neuroinflammation can independently trigger an acquired channelopathy in CA1 pyramidal cell dendrites that alters their integrative properties. By directly changing cellular function, this phenomenon may participate in the phenotypic expression of various brain diseases.
Similar content being viewed by others
References
Beck H, Yaari Y (2008) Plasticity of intrinsic neuronal properties in CNS disorders. Nat Rev Neurosci 9(5):357–369. https://doi.org/10.1038/nrn2371
Santos SF, Pierrot N, Octave JN (2010) Network excitability dysfunction in Alzheimer’s disease: insights from in vitro and in vivo models. Rev Neurosci 21(3):153–171
Chan CS, Glajch KE, Gertler TS, Guzman JN, Mercer JN, Lewis AS, Goldberg AB, Tkatch T et al (2011) HCN channelopathy in external globus pallidus neurons in models of Parkinson’s disease. Nat Neurosci 14(1):85–92. https://doi.org/10.1038/nn.2692
Ng K, Howells J, Pollard JD, Burke D (2008) Up-regulation of slow K(+) channels in peripheral motor axons: a transcriptional channelopathy in multiple sclerosis. Brain 131(11):3062–3071. https://doi.org/10.1093/brain/awn180
Israelson A, Arbel N, Da Cruz S, Ilieva H, Yamanaka K, Shoshan-Barmatz V, Cleveland DW (2010) Misfolded mutant SOD1 directly inhibits VDAC1 conductance in a mouse model of inherited ALS. Neuron 67(4):575–587. https://doi.org/10.1016/j.neuron.2010.07.019
Boadas-Vaello P, Castany S, Homs J, Álvarez-Pérez B, Deulofeu M, Verdú E (2016) Neuroplasticity of ascending and descending pathways after somatosensory system injury: reviewing knowledge to identify neuropathic pain therapeutic targets. Spinal Cord 54(5):330–340. https://doi.org/10.1038/sc.2015.225
Alia C, Spalletti C, Lai S et al (2017) Neuroplastic changes following brain ischemia and their contribution to stroke recovery: novel approaches in neurorehabilitation. Front Cell Neurosci 11:76
Giza CC, Prins ML (2006) Is being plastic fantastic? Mechanisms of altered plasticity after developmental traumatic brain injury. Dev Neurosci 28(4-5):364–379. https://doi.org/10.1159/000094163
Vezzani A, French J, Bartfai T, Baram TZ (2011) The role of inflammation in epilepsy. Nat Rev Neurol 7(1):31–40. https://doi.org/10.1038/nrneurol.2010.178
Xanthos DN, Sandkuhler J (2014) Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat Rev Neurosci 15(1):43–53. https://doi.org/10.1038/nrn3617
Banjara M, Ghosh C (2017) Sterile neuroinflammation and strategies for therapeutic intervention. Int J Inflamm 2017:8385961
Algattas H, Huang JH (2013) Traumatic brain injury pathophysiology and treatments: early, intermediate, and late phases post-injury. Int J Mol Sci 15(1):309–341. https://doi.org/10.3390/ijms15010309
Ransohoff RM, Schafer D, Vincent A, Blachère NE, Bar-Or A (2015) Neuroinflammation: ways in which the immune system affects the brain. Neurotherapeutics 12(4):896–909. https://doi.org/10.1007/s13311-015-0385-3
Vezzani A, Viviani B (2015) Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability. Neuropharmacology 96(Pt A):70–82. https://doi.org/10.1016/j.neuropharm.2014.10.027
Lynch MA (2004) Long-term potentiation and memory. Physiol Rev 84(1):87–136. https://doi.org/10.1152/physrev.00014.2003
Rodgers KM, Hutchinson MR, Northcutt A, Maier SF, Watkins LR, Barth DS (2009) The cortical innate immune response increases local neuronal excitability leading to seizures. Brain 132(9):2478–2486. https://doi.org/10.1093/brain/awp177
Mazarati A, Maroso M, Iori V, Vezzani A, Carli M (2011) High-mobility group box-1 impairs memory in mice through both toll-like receptor 4 and receptor for advanced glycation end products. Exp Neurol 232(2):143–148. https://doi.org/10.1016/j.expneurol.2011.08.012
Riazi K, Galic MA, Pittman QJ (2010) Contributions of peripheral inflammation to seizure susceptibility: cytokines and brain excitability. Epilepsy Res 89(1):34–42. https://doi.org/10.1016/j.eplepsyres.2009.09.004
Bernard C, Anderson A, Becker A, Poolos NP, Beck H, Johnston D (2004) Acquired dendritic channelopathy in temporal lobe epilepsy. Science 305(5683):532–535. https://doi.org/10.1126/science.1097065
Noam Y, Bernard C, Baram TZ (2011) Towards an integrated view of HCN channel role in epilepsy. Curr Opin Neurobiol 21(6):873–879. https://doi.org/10.1016/j.conb.2011.06.013
Kumar P, Kumar D, Jha SK et al (2016) Ion channels in neurological disorders. Adv Protein Chem Struct Biol 103:97–136. https://doi.org/10.1016/bs.apcsb.2015.10.006
Bryant CE, Spring DR, Gangloff M, Gay NJ (2010) The molecular basis of the host response to lipopolysaccharide. Nat Rev Microbiol 8(1):8–14. https://doi.org/10.1038/nrmicro2266
Baruscotti M, Bottelli G, Milanesi R, DiFrancesco JC, DiFrancesco D (2010) HCN-related channelopathies. Pflugers Arch 460(2):405–415. https://doi.org/10.1007/s00424-010-0810-8
Robinson RB, Siegelbaum SA (2003) Hyperpolarization-activated cation currents: From molecules to physiological function. Annu Rev Physiol 65(1):453–480. https://doi.org/10.1146/annurev.physiol.65.092101.142734
Brewster AL, Chen Y, Bender RA et al (2007) Quantitative analysis and subcellular distribution of mRNA and protein expression of the hyperpolarization-activated cyclic nucleotide-gated channels throughout development in rat hippocampus. Cereb Cortex 17:702–712
Magee JC (1999) Dendritic Ih normalizes temporal summation in hippocampal CA1 neurons. Nat Neurosci 2(9):848. https://doi.org/10.1038/12229
George MS, Abbott LF, Siegelbaum SA (2009) HCN hyperpolarization-activated cation channels inhibit EPSPs by interactions with M-type K(+) channels. Nat Neurosci 12(5):577–584. https://doi.org/10.1038/nn.2307
Buzsaki G (2006) Rhythms of the brain. Oxford University Press, New York. https://doi.org/10.1093/acprof:oso/9780195301069.001.0001
Macagno A, Molteni M, Rinaldi A, Bertoni F, Lanzavecchia A, Rossetti C, Sallusto F (2006) A cyanobacterial LPS antagonist prevents endotoxin shock and blocks sustained TLR4 stimulation required for cytokine expression. J Exp Med 203(6):1481–1492. https://doi.org/10.1084/jem.20060136
Maroso M, Balosso S, Ravizza T, Liu J, Aronica E, Iyer AM, Rossetti C, Molteni M et al (2010) Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nat Med 16(4):413–419. https://doi.org/10.1038/nm.2127
Mishto M, Raza ML, de Biase D, Ravizza T, Vasuri F, Martucci M, Keller C, Bellavista E et al (2015) The immunoproteasome Beta5i subunit is key contributor to ictogenesis in a rat model of chronic epilepsy. Brain Behav Immun 49:188–196. https://doi.org/10.1016/j.bbi.2015.05.007
Ravizza T, Gagliardi B, Noé F, Boer K, Aronica E, Vezzani A (2008) Innate and adaptive immunity during epileptogenesis and spontaneous seizures: evidence from experimental models and human temporal lobe epilepsy. Neurobiol Dis 29(1):142–160. https://doi.org/10.1016/j.nbd.2007.08.012
Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates. Academic Press, New York
Walker LE, Frigerio F, Ravizza T, Ricci E, Tse K, Jenkins RE, Sills GJ, Jorgensen A et al (2017) Molecular isoforms of high-mobility group box 1 are mechanistic biomarkers for epilepsy. J Clin Invest 127(6):2118–2132. https://doi.org/10.1172/JCI92001
Shin M, Chetkovich DM (2007) Activity-dependent regulation of h channel distribution in hippocampal CA1 pyramidal neurons. J Biol Chem 282(45):33168–33180. https://doi.org/10.1074/jbc.M703736200
Heuermann RJ, Jaramillo TC, Ying S-W, Suter BA, Lyman KA, Han Y, Lewis AS, Hampton TG et al (2016) Reduction of thalamic and cortical Ih by deletion of TRIP8b produces a mouse model of human absence epilepsy. Neurobiol Dis 85:81–92. https://doi.org/10.1016/j.nbd.2015.10.005
Han Y, Heuermann RJ, Lyman KA, Fisher D, Ismail QA, Chetkovich DM (2017) HCN-channel dendritic targeting requires bipartite interaction with TRIP8b and regulates antidepressant-like behavioral effects. Mol Psychiatry 22(3):458–465. https://doi.org/10.1038/mp.2016.99
Schmued LC, Albertson C, Slikker W (1997) Fluoro-Jade: a novel fluorochrome for the sensitive and reliable histochemical localization of neuronal degeneration. Brain Res 751(1):37–46. https://doi.org/10.1016/S0006-8993(96)01387-X
Marcelin B, Chauvière L, Becker A, Migliore M, Esclapez M, Bernard C (2009) H channel-dependent deficit of theta oscillation resonance and phase shift in temporal lobe epilepsy. Neurobiol Dis 33(3):436–447. https://doi.org/10.1016/j.nbd.2008.11.019
Marcelin B, Lugo JN, Brewster AL, Liu Z, Lewis AS, McClelland S, Chetkovich DM, Baram TZ et al (2012) Differential dorso-ventral distributions of Kv4.2 and HCN proteins confer distinct integrative properties to hippocampal CA1 pyramidal cell distal dendrites. J Biol Chem 287(21):17656–17661. https://doi.org/10.1074/jbc.C112.367110
Lugo JN, Barnwell LF, Ren Y, Lee WL, Johnston LD, Kim R, Hrachovy RA, Sweatt JD et al (2008) Altered phosphorylation and localization of the A-type channel, Kv4.2 in status epilepticus. J Neurochem 106(4):1929–1940. https://doi.org/10.1111/j.1471-4159.2008.05508.x
Dubé CM, Ravizza T, Hamamura M et al (2010) Epileptogenesis provoked by prolonged experimental febrile seizures: mechanisms and biomarkers. J Neurosci 30(22):7484–7494. https://doi.org/10.1523/JNEUROSCI.0551-10.2010
Kirkman NJ, Libbey JE, Wilcox KS, White HS, Fujinami RS (2010) Innate but not adaptive immune responses contribute to behavioral seizures following viral infection. Epilepsia 51(3):454–464. https://doi.org/10.1111/j.1528-1167.2009.02390.x
Viviani B, Bartesaghi S, Gardoni F, Vezzani A, Behrens MM, Bartfai T, Binaglia M, Corsini E et al (2003) Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J Neurosci 23(25):8692–8700
Balosso S, Liu J, Bianchi ME, Vezzani A (2014) Disulfide-containing high mobility group box-1 promotes N-methyl-d-aspartate receptor function and excitotoxicity by activating toll-like receptor 4-dependent signaling in hippocampal neurons. Antioxid Redox Signal 21(12):1726–1740. https://doi.org/10.1089/ars.2013.5349
Jung S, Jones TD, Lugo JN, Sheerin AH, Miller JW, D'Ambrosio R, Anderson AE, Poolos NP (2007) Progressive dendritic HCN channelopathy during epileptogenesis in the rat pilocarpine model of epilepsy. J Neurosci 27(47):13012–13021. https://doi.org/10.1523/JNEUROSCI.3605-07.2007
Shin M, Brager D, Jaramillo TC, Johnston D, Chetkovich DM (2008) Mislocalization of h channel subunits underlies h channelopathy in temporal lobe epilepsy. Neurobiol Dis 32(1):26–36. https://doi.org/10.1016/j.nbd.2008.06.013
McClelland S, Flynn C, Dubé C, Richichi C, Zha Q, Ghestem A, Esclapez M, Bernard C et al (2011) Neuron-restrictive silencer factor-mediated hyperpolarization-activated cyclic nucleotide gated channelopathy in experimental temporal lobe epilepsy. Ann Neurol 70(3):454–464. https://doi.org/10.1002/ana.22479
Lewis AS, Vaidya SP, Blaiss CA, Liu Z, Stoub TR, Brager DH, Chen X, Bender RA et al (2011) Deletion of the hyperpolarization-activated cyclic nucleotide-gated channel auxiliary subunit TRIP8b impairs hippocampal Ih localization and function and promotes antidepressant behavior in mice. J Neurosci 31(20):7424–7440. https://doi.org/10.1523/JNEUROSCI.0936-11.2011
Lyman KA, Han Y, Chetkovich DM (2017) Animal models suggest the TRIP8b-HCN interaction is a therapeutic target for major depressive disorder. Expert Opin Ther Targets 21(3):235–237. https://doi.org/10.1080/14728222.2017.1287899
Surges R, Brewster AL, Bender RA, Beck H, Feuerstein TJ, Baram TZ (2006) Regulated expression of HCN channels and cAMP levels shape the properties of the h current in developing rat hippocampus. Eur J Neurosci 24(1):94–104. https://doi.org/10.1111/j.1460-9568.2006.04880.x
Narayanan R, Johnston D (2007) Long-term potentiation in rat hippocampal neurons is accompanied by spatially widespread changes in intrinsic oscillatory dynamics and excitability. Neuron 56(6):1061–1075. https://doi.org/10.1016/j.neuron.2007.10.033
Narayanan R, Johnston D (2008) The h channel mediates location dependence and plasticity of intrinsic phase response in rat hippocampal neurons. J Neurosci 28(22):5846–5860. https://doi.org/10.1523/JNEUROSCI.0835-08.2008
Notomi T, Shigemoto R (2004) Immunohistochemical localization of Ih channel subunits, HCN1-4, in the rat brain. J Comp Neurol 471(3):241–276. https://doi.org/10.1002/cne.11039
Jung S, Warner LN, Pitsch J, Becker AJ, Poolos NP (2011) Rapid loss of dendritic HCN channel expression in hippocampal pyramidal neurons following status epilepticus. J Neurosci 31(40):14291–14295. https://doi.org/10.1523/JNEUROSCI.1148-11.2011
O’Neill LA, Bowie AG (2007) The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol 7(5):353–364. https://doi.org/10.1038/nri2079
Flegel WA, Baumstark MW, Weinstock C, Berg A, Northoff H (1993) Prevention of endotoxin-induced monokine release by human low- and high-density lipoproteins and by apolipoprotein A-I. Infect Immun 61(12):5140–5146
Roseti C, van Vliet EA, Cifelli P, Ruffolo G, Baayen JC, di Castro MA, Bertollini C, Limatola C et al (2015) GABA currents are decreased by IL-1beta in epileptogenic tissue of patients with temporal lobe epilepsy: Implications for ictogenesis. Neurobiol Dis 82:311–320. https://doi.org/10.1016/j.nbd.2015.07.003
Iori V, Maroso M, Rizzi M, Iyer AM, Vertemara R, Carli M, Agresti A, Antonelli A et al (2013) Receptor for advanced Glycation Endproducts is upregulated in temporal lobe epilepsy and contributes to experimental seizures. Neurobiol Dis 58:102–114. https://doi.org/10.1016/j.nbd.2013.03.006
Chen K, Sun Y, Diao Y, Ji L, Song D, Zhang T (2017) α7 nicotinic acetylcholine receptor agonist inhibits the damage of rat hippocampal neurons by TLR4/Myd88/NF-κB signaling pathway during cardiopulmonary bypass. Mol Med Rep 16(4):4770–4776. https://doi.org/10.3892/mmr.2017.7166
Garay-Malpartida HM, Mourão RF, Mantovani M, Santos IA, Sogayar MC, Goldberg AC (2011) Toll-like receptor 4 (TLR4) expression in human and murine pancreatic beta-cells affects cell viability and insulin homeostasis. BMC Immunol 12(1):18. https://doi.org/10.1186/1471-2172-12-18
Wang J, Feng X, Zeng Y, Fan J, Wu J, Li Z, Liu X, Huang R et al (2013) Lipopolysaccharide (LPS)-induced autophagy is involved in the restriction of Escherichia coli in peritoneal mesothelial cells. BMC Microbiol 13(1):255. https://doi.org/10.1186/1471-2180-13-255
Badshah H, Ali T, Kim MO (2016) Osmotin attenuates LPS-induced neuroinflammation and memory impairments via the TLR4/NFκB signaling pathway. Sci Rep 6(1):24493. https://doi.org/10.1038/srep24493
Chen K, Aradi I, Thon N, Eghbal-Ahmadi M, Baram TZ, Soltesz I (2001) Persistently modified h-channels after complex febrile seizures convert the seizure-induced enhancement of inhibition to hyperexcitability. Nat Med 7(3):331–337. https://doi.org/10.1038/85480
Chauvière L, Rafrafi N, Thinus-Blanc C et al (2009) Early deficits in spatial memory and theta rhythm in experimental temporal lobe epilepsy. J Neurosci 29(17):5402–5410. https://doi.org/10.1523/JNEUROSCI.4699-08.2009
Cunningham C, Sanderson DJ (2008) Malaise in the water maze: untangling the effects of LPS and IL-1beta on learning and memory. Brain Behav Immun 22(8):1117–1127. https://doi.org/10.1016/j.bbi.2008.05.007
Terrando N, Rei Fidalgo A, Vizcaychipi M, Cibelli M, Ma D, Monaco C, Feldmann M, Maze M (2010) The impact of IL-1 modulation on the development of lipopolysaccharide-induced cognitive dysfunction. Crit Care 14(3):R88. https://doi.org/10.1186/cc9019
Valdés-Ferrer SI, Rosas-Ballina M, Olofsson PS, Lu B, Dancho ME, Li JH, Yang H, Pavlov VA et al (2013) High-mobility group box 1 mediates persistent splenocyte priming in sepsis survivors: evidence from a murine model. Shock 40(6):492–495. https://doi.org/10.1097/SHK.0000000000000050
Uhlhaas PJ, Singer W (2006) Neural synchrony in brain disorders: relevance for cognitive dysfunctions and pathophysiology. Neuron 52(1):155–168. https://doi.org/10.1016/j.neuron.2006.09.020
Vlooswijk MC, Jansen JF, de Krom MC et al (2010) Functional MRI in chronic epilepsy: associations with cognitive impairment. Lancet Neurol 9(10):1018–1027. https://doi.org/10.1016/S1474-4422(10)70180-0
Zorn-Pauly K, Pelzmann B, Lang P, Mächler H, Schmidt H, Ebelt H, Werdan K, Koidl B et al (2007) Endotoxin impairs the human pacemaker current If. Shock 28(6):655–661
Acknowledgements
We thank Amy L. Brewster and Francesco Noé for their contribution to the initial experiments.
Funding
This work was supported by INSERM, ANR MINOS, and ANTARES (C.B.), and the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement n°602102 (EPITARGET to C.B. and A.V.), C.F. was supported by an Alberta Heritage Foundation for Medical Research (AHFMR) Fellowship. Additionally, this work was supported by Fondazione Italo Monzino (A.V.), National Institutes of Health Grant 2R01NS059934, R01MH106511, and R21MH104471 (D.M.C).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
Fig. S1
IL-1β expressing microglia in the rat hippocampus after LPS. a–d Representative photomicrographs showing the progressive changes in IL-1β immunoreactivity in the rat septal hippocampus at various times (n = 4–12 rats) after bilateral icv LPS injection (25 μg/2 μl) vs vehicle injection (n = 2–8 rats). Six hours after LPS injection (b), IL-1β immunostaining was increased in the hippocampal regions adjacent to the ventricular area. IL-1β signal was strongly induced throughout the whole hippocampus at 24 h (c) post-LPS, then declining by 1 week (d) to undetectable levels as in sham controls (a). The merge images (e, f) show co-localization of IL-1β signal with the microglia marker OX-42 (yellow signal in e) but not with the astrocytic marker GFAP (f). Bargram in (g) depicts the quantification of IL-1β expression 24 h post-LPS (area occupied by the specific signal/total area analyzed). CA1, CA3 pyramidal cell layers, h hilus. Scale bar: a–d, 220 μm; e, f 25 μm (GIF 123 kb)
Fig. S2
Treatment with LPS causes a reduction in total hippocampal HCN1 protein but not TRIP8b. Western blots were performed from whole hippocampi of rats treated with either vehicle or LPS (n = 5 each experimental group). A significant reduction in HCN1 (a, b) was observed without a difference in TRIP8b (c, d). Data are mean ± s.e.m. *p < 0.05 by Mann–Whitney test (GIF 91 kb)
Fig S3
Blockade of LPS effects by the selective TLR4 antagonist Cyanobacterial LPS. Rats were injected icv with Cyanobacterial LPS (CyP; 60 μg/3 μl in PBS, bilaterally) 15 min before and 15 min after icv LPS injection (25 μg/2 μl in PBS bilaterally). Rats were sacrificed 24 h after LPS injection. a A significant reduction of IL-1β staining was observed by immunohistochemistry in rats treated with LPS + CyP vs LPS alone (n = 5 rats each group). CA1, CA1 pyramidal neurons, CA3, CA3 pyramidal neurons, h hilus. Scale bar 250 μm. b LPS-induced reduction of HCN1 was prevented by CyP as assessed by western blot. Data are mean ± s.e.m. (n = 8–9 rats). *p < 0.05 by Kruskal-Wallis followed by Dunn’s post-hoc test (GIF 86 kb)
Rights and permissions
About this article
Cite this article
Frigerio, F., Flynn, C., Han, Y. et al. Neuroinflammation Alters Integrative Properties of Rat Hippocampal Pyramidal Cells. Mol Neurobiol 55, 7500–7511 (2018). https://doi.org/10.1007/s12035-018-0915-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12035-018-0915-1