--- _id: '9097' abstract: - lang: eng text: Psoriasis is a chronic inflammatory skin disease clinically characterized by the appearance of red colored, well-demarcated plaques with thickened skin and with silvery scales. Recent studies have established the involvement of a complex signalling network of interactions between cytokines, immune cells and skin cells called keratinocytes. Keratinocytes form the cells of the outermost layer of the skin (epidermis). Visible plaques in psoriasis are developed due to the fast proliferation and unusual differentiation of keratinocyte cells. Despite that, the exact mechanism of the appearance of these plaques in the cytokine-immune cell network is not clear. A mathematical model embodying interactions between key immune cells believed to be involved in psoriasis, keratinocytes and relevant cytokines has been developed. The complex network formed of these interactions poses several challenges. Here, we choose to study subnetworks of this complex network and initially focus on interactions involving TNFα, IL-23/IL-17, and IL-15. These are chosen based on known evidence of their therapeutic efficacy. In addition, we explore the role of IL-15 in the pathogenesis of psoriasis and its potential as a future drug target for a novel treatment option. We perform steady state analyses for these subnetworks and demonstrate that the interactions between cells, driven by cytokines could cause the emergence of a psoriasis state (hyper-proliferation of keratinocytes) when levels of TNFα, IL-23/IL-17 or IL-15 are increased. The model results explain and support the clinical potentiality of anti-cytokine treatments. Interestingly, our results suggest different dynamic scenarios underpin the pathogenesis of psoriasis, depending upon the dominant cytokines of subnetworks. We observed that the increase in the level of IL-23/IL-17 and IL-15 could lead to psoriasis via a bistable route, whereas an increase in the level of TNFα would lead to a monotonic and gradual disease progression. Further, we demonstrate how this insight, bistability, could be exploited to improve the current therapies and develop novel treatment strategies for psoriasis. acknowledgement: RP acknowledges the Department of Science and Technology, India for the support through the DST-INSPIRE Faculty Award (DST/INSPIRE/04/2015/001939). This work was supported by the Engineering and Physical Sciences Research Council (EPSRC), United Kingdom (Grant numbers EP/J018295/1, EP/J018392/1, EP/N014391/1). The contribution of RP was also supported by the later Grant. This work was generously supported by the Welcome Trust Institutional Strategic Support Award (204909/Z/16/Z) too. The contribution of MG was supported by the EPSRC via EP/N014391/1 and a Wellcome Trust Institutional Strategic Support Award (WT105618MA). The contribution of YA was generously supported by the Wellcome Trust Institutional Strategic Support Award (WT105618MA). article_number: '2204' article_processing_charge: No article_type: original author: - first_name: Rakesh full_name: Pandey, Rakesh last_name: Pandey - first_name: Yusur full_name: Al-Nuaimi, Yusur last_name: Al-Nuaimi - first_name: Rajiv Kumar full_name: Mishra, Rajiv Kumar id: 46CB58F2-F248-11E8-B48F-1D18A9856A87 last_name: Mishra - first_name: Sarah K. full_name: Spurgeon, Sarah K. last_name: Spurgeon - first_name: Marc full_name: Goodfellow, Marc last_name: Goodfellow citation: ama: Pandey R, Al-Nuaimi Y, Mishra RK, Spurgeon SK, Goodfellow M. Role of subnetworks mediated by TNF α, IL-23/IL-17 and IL-15 in a network involved in the pathogenesis of psoriasis. Scientific Reports. 2021;11. doi:10.1038/s41598-020-80507-7 apa: Pandey, R., Al-Nuaimi, Y., Mishra, R. K., Spurgeon, S. K., & Goodfellow, M. (2021). Role of subnetworks mediated by TNF α, IL-23/IL-17 and IL-15 in a network involved in the pathogenesis of psoriasis. Scientific Reports. Springer Nature. https://doi.org/10.1038/s41598-020-80507-7 chicago: Pandey, Rakesh, Yusur Al-Nuaimi, Rajiv Kumar Mishra, Sarah K. Spurgeon, and Marc Goodfellow. “Role of Subnetworks Mediated by TNF α, IL-23/IL-17 and IL-15 in a Network Involved in the Pathogenesis of Psoriasis.” Scientific Reports. Springer Nature, 2021. https://doi.org/10.1038/s41598-020-80507-7. ieee: R. Pandey, Y. Al-Nuaimi, R. K. Mishra, S. K. Spurgeon, and M. Goodfellow, “Role of subnetworks mediated by TNF α, IL-23/IL-17 and IL-15 in a network involved in the pathogenesis of psoriasis,” Scientific Reports, vol. 11. Springer Nature, 2021. ista: Pandey R, Al-Nuaimi Y, Mishra RK, Spurgeon SK, Goodfellow M. 2021. Role of subnetworks mediated by TNF α, IL-23/IL-17 and IL-15 in a network involved in the pathogenesis of psoriasis. Scientific Reports. 11, 2204. mla: Pandey, Rakesh, et al. “Role of Subnetworks Mediated by TNF α, IL-23/IL-17 and IL-15 in a Network Involved in the Pathogenesis of Psoriasis.” Scientific Reports, vol. 11, 2204, Springer Nature, 2021, doi:10.1038/s41598-020-80507-7. short: R. Pandey, Y. Al-Nuaimi, R.K. Mishra, S.K. Spurgeon, M. Goodfellow, Scientific Reports 11 (2021). date_created: 2021-02-07T23:01:12Z date_published: 2021-01-26T00:00:00Z date_updated: 2022-08-19T07:22:23Z day: '26' ddc: - '570' department: - _id: PeJo doi: 10.1038/s41598-020-80507-7 file: - access_level: open_access checksum: e8a68df48750712671f5c47b0228e531 content_type: application/pdf creator: dernst date_created: 2021-02-09T07:33:23Z date_updated: 2021-02-09T07:33:23Z file_id: '9106' file_name: 2021_ScientificReports_Pandey.pdf file_size: 2885056 relation: main_file success: 1 file_date_updated: 2021-02-09T07:33:23Z has_accepted_license: '1' intvolume: ' 11' language: - iso: eng month: '01' oa: 1 oa_version: Published Version publication: Scientific Reports publication_identifier: eissn: - '20452322' publication_status: published publisher: Springer Nature quality_controlled: '1' scopus_import: '1' status: public title: Role of subnetworks mediated by TNF α, IL-23/IL-17 and IL-15 in a network involved in the pathogenesis of psoriasis tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 volume: 11 year: '2021' ... --- _id: '1432' abstract: - lang: eng text: CA3–CA3 recurrent excitatory synapses are thought to play a key role in memory storage and pattern completion. Whether the plasticity properties of these synapses are consistent with their proposed network functions remains unclear. Here, we examine the properties of spike timing-dependent plasticity (STDP) at CA3–CA3 synapses. Low-frequency pairing of excitatory postsynaptic potentials (EPSPs) and action potentials (APs) induces long-term potentiation (LTP), independent of temporal order. The STDP curve is symmetric and broad (half-width ~150 ms). Consistent with these STDP induction properties, AP–EPSP sequences lead to supralinear summation of spine [Ca2+] transients. Furthermore, afterdepolarizations (ADPs) following APs efficiently propagate into dendrites of CA3 pyramidal neurons, and EPSPs summate with dendritic ADPs. In autoassociative network models, storage and recall are more robust with symmetric than with asymmetric STDP rules. Thus, a specialized STDP induction rule allows reliable storage and recall of information in the hippocampal CA3 network. acknowledgement: 'We thank Jozsef Csicsvari and Nelson Spruston for critically reading the manuscript. We also thank A. Schlögl for programming, F. Marr for technical assistance and E. Kramberger for manuscript editing. ' article_number: '11552' author: - first_name: Rajiv Kumar full_name: Mishra, Rajiv Kumar id: 46CB58F2-F248-11E8-B48F-1D18A9856A87 last_name: Mishra - first_name: Sooyun full_name: Kim, Sooyun id: 394AB1C8-F248-11E8-B48F-1D18A9856A87 last_name: Kim - first_name: José full_name: Guzmán, José id: 30CC5506-F248-11E8-B48F-1D18A9856A87 last_name: Guzmán orcid: 0000-0003-2209-5242 - first_name: Peter M full_name: Jonas, Peter M id: 353C1B58-F248-11E8-B48F-1D18A9856A87 last_name: Jonas orcid: 0000-0001-5001-4804 citation: ama: Mishra RK, Kim S, Guzmán J, Jonas PM. Symmetric spike timing-dependent plasticity at CA3–CA3 synapses optimizes storage and recall in autoassociative networks. Nature Communications. 2016;7. doi:10.1038/ncomms11552 apa: Mishra, R. K., Kim, S., Guzmán, J., & Jonas, P. M. (2016). Symmetric spike timing-dependent plasticity at CA3–CA3 synapses optimizes storage and recall in autoassociative networks. Nature Communications. Nature Publishing Group. https://doi.org/10.1038/ncomms11552 chicago: Mishra, Rajiv Kumar, Sooyun Kim, José Guzmán, and Peter M Jonas. “Symmetric Spike Timing-Dependent Plasticity at CA3–CA3 Synapses Optimizes Storage and Recall in Autoassociative Networks.” Nature Communications. Nature Publishing Group, 2016. https://doi.org/10.1038/ncomms11552. ieee: R. K. Mishra, S. Kim, J. Guzmán, and P. M. Jonas, “Symmetric spike timing-dependent plasticity at CA3–CA3 synapses optimizes storage and recall in autoassociative networks,” Nature Communications, vol. 7. Nature Publishing Group, 2016. ista: Mishra RK, Kim S, Guzmán J, Jonas PM. 2016. Symmetric spike timing-dependent plasticity at CA3–CA3 synapses optimizes storage and recall in autoassociative networks. Nature Communications. 7, 11552. mla: Mishra, Rajiv Kumar, et al. “Symmetric Spike Timing-Dependent Plasticity at CA3–CA3 Synapses Optimizes Storage and Recall in Autoassociative Networks.” Nature Communications, vol. 7, 11552, Nature Publishing Group, 2016, doi:10.1038/ncomms11552. short: R.K. Mishra, S. Kim, J. Guzmán, P.M. Jonas, Nature Communications 7 (2016). date_created: 2018-12-11T11:51:59Z date_published: 2016-05-13T00:00:00Z date_updated: 2023-09-07T11:55:25Z day: '13' ddc: - '570' department: - _id: PeJo doi: 10.1038/ncomms11552 ec_funded: 1 file: - access_level: open_access checksum: 7e84d0392348c874d473b62f1042de22 content_type: application/pdf creator: system date_created: 2018-12-12T10:18:33Z date_updated: 2020-07-14T12:44:53Z file_id: '5355' file_name: IST-2016-582-v1+1_ncomms11552.pdf file_size: 4510512 relation: main_file file_date_updated: 2020-07-14T12:44:53Z has_accepted_license: '1' intvolume: ' 7' language: - iso: eng month: '05' oa: 1 oa_version: Published Version project: - _id: 25C26B1E-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: P24909-B24 name: Mechanisms of transmitter release at GABAergic synapses - _id: 25C0F108-B435-11E9-9278-68D0E5697425 call_identifier: FP7 grant_number: '268548' name: Nanophysiology of fast-spiking, parvalbumin-expressing GABAergic interneurons publication: Nature Communications publication_status: published publisher: Nature Publishing Group publist_id: '5766' pubrep_id: '582' quality_controlled: '1' related_material: record: - id: '1396' relation: dissertation_contains status: public scopus_import: 1 status: public title: Symmetric spike timing-dependent plasticity at CA3–CA3 synapses optimizes storage and recall in autoassociative networks tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 3E5EF7F0-F248-11E8-B48F-1D18A9856A87 volume: 7 year: '2016' ... --- _id: '1396' abstract: - lang: eng text: CA3 pyramidal neurons are thought to pay a key role in memory storage and pattern completion by activity-dependent synaptic plasticity between CA3-CA3 recurrent excitatory synapses. To examine the induction rules of synaptic plasticity at CA3-CA3 synapses, we performed whole-cell patch-clamp recordings in acute hippocampal slices from rats (postnatal 21-24 days) at room temperature. Compound excitatory postsynaptic potentials (ESPSs) were recorded by tract stimulation in stratum oriens in the presence of 10 µM gabazine. High-frequency stimulation (HFS) induced N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP). Although LTP by HFS did not requier postsynaptic spikes, it was blocked by Na+-channel blockers suggesting that local active processes (e.g.) dendritic spikes) may contribute to LTP induction without requirement of a somatic action potential (AP). We next examined the properties of spike timing-dependent plasticity (STDP) at CA3-CA3 synapses. Unexpectedly, low-frequency pairing of EPSPs and backpropagated action potentialy (bAPs) induced LTP, independent of temporal order. The STDP curve was symmetric and broad, with a half-width of ~150 ms. Consistent with these specific STDP induction properties, post-presynaptic sequences led to a supralinear summation of spine [Ca2+] transients. Furthermore, in autoassociative network models, storage and recall was substantially more robust with symmetric than with asymmetric STDP rules. In conclusion, we found associative forms of LTP at CA3-CA3 recurrent collateral synapses with distinct induction rules. LTP induced by HFS may be associated with dendritic spikes. In contrast, low frequency pairing of pre- and postsynaptic activity induced LTP only if EPSP-AP were temporally very close. Together, these induction mechanisms of synaptiic plasticity may contribute to memory storage in the CA3-CA3 microcircuit at different ranges of activity. alternative_title: - ISTA Thesis article_processing_charge: No author: - first_name: Rajiv Kumar full_name: Mishra, Rajiv Kumar id: 46CB58F2-F248-11E8-B48F-1D18A9856A87 last_name: Mishra citation: ama: Mishra RK. Synaptic plasticity rules at CA3-CA3 recurrent synapses in hippocampus. 2016. apa: Mishra, R. K. (2016). Synaptic plasticity rules at CA3-CA3 recurrent synapses in hippocampus. Institute of Science and Technology Austria. chicago: Mishra, Rajiv Kumar. “Synaptic Plasticity Rules at CA3-CA3 Recurrent Synapses in Hippocampus.” Institute of Science and Technology Austria, 2016. ieee: R. K. Mishra, “Synaptic plasticity rules at CA3-CA3 recurrent synapses in hippocampus,” Institute of Science and Technology Austria, 2016. ista: Mishra RK. 2016. Synaptic plasticity rules at CA3-CA3 recurrent synapses in hippocampus. Institute of Science and Technology Austria. mla: Mishra, Rajiv Kumar. Synaptic Plasticity Rules at CA3-CA3 Recurrent Synapses in Hippocampus. Institute of Science and Technology Austria, 2016. short: R.K. Mishra, Synaptic Plasticity Rules at CA3-CA3 Recurrent Synapses in Hippocampus, Institute of Science and Technology Austria, 2016. date_created: 2018-12-11T11:51:46Z date_published: 2016-03-01T00:00:00Z date_updated: 2023-09-07T11:55:26Z day: '01' ddc: - '570' degree_awarded: PhD department: - _id: PeJo file: - access_level: closed checksum: 5a010a838faf040f7064f3cfb802f743 content_type: application/pdf creator: dernst date_created: 2019-08-09T12:14:46Z date_updated: 2020-07-14T12:44:48Z file_id: '6782' file_name: Thesis_Mishra_Rajiv (Final).pdf file_size: 2407572 relation: main_file - access_level: open_access checksum: 81b26d9ede92c99f1d8cc6fa1d04cbbb content_type: application/pdf creator: dernst date_created: 2021-02-22T11:48:44Z date_updated: 2021-02-22T11:48:44Z file_id: '9183' file_name: 2016_RajivMishra_Thesis.pdf file_size: 2407572 relation: main_file success: 1 file_date_updated: 2021-02-22T11:48:44Z has_accepted_license: '1' language: - iso: eng month: '03' oa: 1 oa_version: Published Version page: '83' publication_identifier: issn: - 2663-337X publication_status: published publisher: Institute of Science and Technology Austria publist_id: '5811' related_material: record: - id: '1432' relation: part_of_dissertation status: public status: public supervisor: - first_name: Peter M full_name: Jonas, Peter M id: 353C1B58-F248-11E8-B48F-1D18A9856A87 last_name: Jonas orcid: 0000-0001-5001-4804 title: Synaptic plasticity rules at CA3-CA3 recurrent synapses in hippocampus type: dissertation user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1 year: '2016' ...