Hippocampal extracellular matrix alterations contribute to cognitive impairment associated with a chronic depressive-like state in rats

Danai Riga; Ioannis Kramvis; Maija K Koskinen; Pieter van Bokhoven; Johanneke E van der Harst; Tim S Heistek; A Jaap Timmerman; Pim van Nierop; Roel C van der Schors; Anton W Pieneman; Anouk de Weger; Yvar van Mourik; Anton N M Schoffelmeer; Huib D Mansvelder; Rhiannon M Meredith; Witte J G Hoogendijk; August B Smit; Sabine Spijker

doi:10.1126/scitranslmed.aai8753

Hippocampal extracellular matrix alterations contribute to cognitive impairment associated with a chronic depressive-like state in rats

Danai Riga, Ioannis Kramvis, Maija K Koskinen, Pieter van Bokhoven, Johanneke E van der Harst, Tim S Heistek, A Jaap Timmerman, Pim van Nierop, Roel C van der Schors, Anton W Pieneman, Anouk de Weger, Yvar van Mourik, Anton N M Schoffelmeer, Huib D Mansvelder, Rhiannon M Meredith, Witte J G Hoogendijk, August B Smit, Sabine Spijker

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Abstract

Patients with depression often suffer from cognitive impairments that contribute to disease burden. We used social defeat-induced persistent stress (SDPS) to induce a depressive-like state in rats and then studied long-lasting memory deficits in the absence of acute stressors in these animals. The SDPS rat model showed reduced short-term object location memory and maintenance of long-term potentiation (LTP) in CA1 pyramidal neurons of the dorsal hippocampus. SDPS animals displayed increased expression of synaptic chondroitin sulfate proteoglycans in the dorsal hippocampus. These effects were abrogated by a 3-week treatment with the antidepressant imipramine starting 8 weeks after the last defeat encounter. Next, we observed an increase in the number of perineuronal nets (PNNs) surrounding parvalbumin-expressing interneurons and a decrease in the frequency of inhibitory postsynaptic currents (IPSCs) in the hippocampal CA1 region in SDPS animals. In vivo breakdown of the hippocampus CA1 extracellular matrix by the enzyme chondroitinase ABC administered intracranially restored the number of PNNs, LTP maintenance, hippocampal inhibitory tone, and memory performance on the object place recognition test. Our data reveal a causal link between increased hippocampal extracellular matrix and the cognitive deficits associated with a chronic depressive-like state in rats exposed to SDPS.

Original language	English
Article number	eaai8753
Pages (from-to)	1-12
Number of pages	12
Journal	Science Translational Medicine
Volume	9
Issue number	421
Early online date	20 Dec 2017
DOIs	https://doi.org/10.1126/scitranslmed.aai8753
Publication status	Published - Dec 2017

Funding

We thank J. Cornelis for the help with the proteomics pipeline, T. J. Theijs for the help with immunohistochemical staining, T. Gebuis for the help with the immunohistochemical analysis, D. Schetters for the excellent biotechnical assistance, and M. van den Oever for the valuable advice on the manuscript. Funding: D.R. received funding from the Center for Neurogenomics and Cognitive Research. P.v.B., A.B.S., W.J.G.H., and S.S. received funding from the Top Institute Pharma project T5-203. A.B.S. and S.S. received partial funding from the Center for Medical Systems Biology (CMSB). S.S. received funding from ALW-Vici 016.150.673/865.14.002. Author contributions: P.v.B., D.R., W.J.G.H., A.B.S., and S.S. designed the proteomic experiments and biochemical validations. D.R., P.v.B., and R.C.v.d.S. executed the proteomic experiments and biochemical validations. D.R., P.v.N., and S.S. analyzed the proteomic experiments and biochemical validations. D.R., A.B.S., and S.S. designed the immunohistochemical experiments. D.R., M.K.K., and A.d.W. executed and analyzed the immunohistochemical experiments. I.K., P.v.B., D.R., R.M.M., H.D.M., A.B.S., and S.S. designed the physiological experiments. I.K., A.J.T., T.S.H., and P.v.B. executed the physiological experiments. I.K., S.S., R.M.M., A.J.T., T.S.H., and H.D.M. analyzed the physiological experiments. P.v.B., J.E.v.d.H., D.R., W.J.G.H., A.B.S., and S.S. designed the behavioral experiments. D.R., P.v.B., and J.E.v.d.H. executed the behavioral experiments. D.R., P.v.B., J.E.v.d.H., and S.S. analyzed the behavioral experiments. D.R., A.N.M.S., A.B.S., and S.S. designed the intervention (chondroitinase ABC) experiments. D.R. and Y.v.M. performed the intervention. D.R. performed the behavioral readout of the intervention. M.K.K. performed the immunohistochemical readout of the intervention. I.K., A.J.T., and A.W.P. executed the physiological readout of the intervention experiment. D.R., I.K., M.K.K., A.J.T., and S.S. analyzed the data for the intervention experiments. D.R., A.B.S., and S.S. wrote the manuscript. Competing interests: A.B.S. and S.S. are co-inventors on pending patent #P100640EP00 “Treatment of cognitive impairment in depressive disorders.” J.E.v.d.H. is currently employed at Danone Nutricia Research (Utrecht) and at Noldus Information Technology (Wageningen). A.B.S. participates in a holding that owns shares of Sylics BV. P.v.B. is currently employed as a business developer at the Neuroscience Campus Amsterdam VU Medical Center. All other authors declare that they have no competing interests.

Funders	Funder number
Top Institute Pharma	T5-203

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Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Hippocampal extracellular matrix alterations contribute to cognitive impairment associated with a chronic depressive-like state in ratsFinal published version, 944 KBLicence: Article 25fa Dutch Copyright Act

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Riga, D., Kramvis, I., Koskinen, M. K., van Bokhoven, P., van der Harst, J. E., Heistek, T. S., Jaap Timmerman, A., van Nierop, P., van der Schors, R. C., Pieneman, A. W., de Weger, A., van Mourik, Y., Schoffelmeer, A. N. M., Mansvelder, H. D., Meredith, R. M., Hoogendijk, W. J. G., Smit, A. B., & Spijker, S. (2017). Hippocampal extracellular matrix alterations contribute to cognitive impairment associated with a chronic depressive-like state in rats. Science Translational Medicine, 9(421), 1-12. Article eaai8753. https://doi.org/10.1126/scitranslmed.aai8753

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title = "Hippocampal extracellular matrix alterations contribute to cognitive impairment associated with a chronic depressive-like state in rats",

abstract = "Patients with depression often suffer from cognitive impairments that contribute to disease burden. We used social defeat-induced persistent stress (SDPS) to induce a depressive-like state in rats and then studied long-lasting memory deficits in the absence of acute stressors in these animals. The SDPS rat model showed reduced short-term object location memory and maintenance of long-term potentiation (LTP) in CA1 pyramidal neurons of the dorsal hippocampus. SDPS animals displayed increased expression of synaptic chondroitin sulfate proteoglycans in the dorsal hippocampus. These effects were abrogated by a 3-week treatment with the antidepressant imipramine starting 8 weeks after the last defeat encounter. Next, we observed an increase in the number of perineuronal nets (PNNs) surrounding parvalbumin-expressing interneurons and a decrease in the frequency of inhibitory postsynaptic currents (IPSCs) in the hippocampal CA1 region in SDPS animals. In vivo breakdown of the hippocampus CA1 extracellular matrix by the enzyme chondroitinase ABC administered intracranially restored the number of PNNs, LTP maintenance, hippocampal inhibitory tone, and memory performance on the object place recognition test. Our data reveal a causal link between increased hippocampal extracellular matrix and the cognitive deficits associated with a chronic depressive-like state in rats exposed to SDPS.",

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note = "Copyright {\textcopyright} 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.",

year = "2017",

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doi = "10.1126/scitranslmed.aai8753",

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Riga, D, Kramvis, I, Koskinen, MK, van Bokhoven, P, van der Harst, JE, Heistek, TS , Jaap Timmerman, A, van Nierop, P, van der Schors, RC, Pieneman, AW, de Weger, A, van Mourik, Y, Schoffelmeer, ANM, Mansvelder, HD, Meredith, RM, Hoogendijk, WJG, Smit, AB & Spijker, S 2017, 'Hippocampal extracellular matrix alterations contribute to cognitive impairment associated with a chronic depressive-like state in rats', Science Translational Medicine, vol. 9, no. 421, eaai8753, pp. 1-12. https://doi.org/10.1126/scitranslmed.aai8753

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AU - Riga, Danai

AU - Kramvis, Ioannis

AU - Koskinen, Maija K

AU - van Bokhoven, Pieter

AU - van der Harst, Johanneke E

AU - Heistek, Tim S

AU - Jaap Timmerman, A

AU - van Nierop, Pim

AU - van der Schors, Roel C

AU - Pieneman, Anton W

AU - de Weger, Anouk

AU - van Mourik, Yvar

AU - Schoffelmeer, Anton N M

AU - Mansvelder, Huib D

AU - Meredith, Rhiannon M

AU - Hoogendijk, Witte J G

AU - Smit, August B

AU - Spijker, Sabine

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N2 - Patients with depression often suffer from cognitive impairments that contribute to disease burden. We used social defeat-induced persistent stress (SDPS) to induce a depressive-like state in rats and then studied long-lasting memory deficits in the absence of acute stressors in these animals. The SDPS rat model showed reduced short-term object location memory and maintenance of long-term potentiation (LTP) in CA1 pyramidal neurons of the dorsal hippocampus. SDPS animals displayed increased expression of synaptic chondroitin sulfate proteoglycans in the dorsal hippocampus. These effects were abrogated by a 3-week treatment with the antidepressant imipramine starting 8 weeks after the last defeat encounter. Next, we observed an increase in the number of perineuronal nets (PNNs) surrounding parvalbumin-expressing interneurons and a decrease in the frequency of inhibitory postsynaptic currents (IPSCs) in the hippocampal CA1 region in SDPS animals. In vivo breakdown of the hippocampus CA1 extracellular matrix by the enzyme chondroitinase ABC administered intracranially restored the number of PNNs, LTP maintenance, hippocampal inhibitory tone, and memory performance on the object place recognition test. Our data reveal a causal link between increased hippocampal extracellular matrix and the cognitive deficits associated with a chronic depressive-like state in rats exposed to SDPS.

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Hippocampal extracellular matrix alterations contribute to cognitive impairment associated with a chronic depressive-like state in rats

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