Impairment of synaptic plasticity by the stress mediator CRH involves selective destruction of thin dendritic spines via RhoA signaling
Open accessAbstract
Stress is ubiquitous in modern life and exerts profound effects on cognitive and emotional functions. Thus, whereas acute stress enhances memory, longer episodes exert negative effects through as yet unresolved mechanisms. We report a novel, hippocampus-intrinsic mechanism for the selective memory defects that are provoked by stress. CRH (corticotropin-releasing hormone), a peptide released from hippocampal neurons during stress, depressed synaptic transmission, blocked activity-induced polymerization of spine actin and impaired synaptic plasticity in adult hippocampal slices. Live, multiphoton imaging demonstrated a selective vulnerability of thin dendritic spines to this stress hormone, resulting in depletion of small, potentiation-ready excitatory synapses. The underlying molecular mechanisms required activation and signaling of the actin-regulating small GTPase, RhoA. These results implicate the selective loss of dendritic spine sub-populations as a novel structural and functional foundation for the clinically important effects of stress on cognitive and emotional processes.
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PSD-95 localizes to the heads of GFP-expressing dendritic spines of hippocampal pyramidal neurons, so counts of PSD-95 puncta provide a measure of dendritic spines and synapses.
“PSD-95 localized to the heads of GFP-expressing dendritic spines of hippocampal pyramidal neurons, (Figure 2c), so that counts of PSD-95 puncta provided a measure of dendritic spines and synapses.31”
From Preferential loss of dorsal-hippocampus synapses underlies memory impairments provoked by short, multimodal stress (2014) · cites this paper as [31]
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Cites
Effects of stress throughout the lifespan on the brain, behaviour and cognition
Lupien, S. J., McEwen, B. S., Gunnar, M. R., & Heim, C. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2639 · Cited by 6,256 · see citing works
Stress and the brain: from adaptation to disease
de Kloet, E. R., Joëls, M., & Holsboer, F. (2005) · Nature Reviews Neuroscience · doi:10.1038/nrn1683 · Cited by 4,621 · see citing works
AMPA Receptor Trafficking and Synaptic Plasticity
Malinow, R., & Malenka, R. C. (2002) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.25.112701.142758 · Cited by 2,588 · see citing works
The Medial Temporal Lobe and Recognition Memory
Eichenbaum, H., Yonelinas, A. P., & Ranganath, C. (2007) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.30.051606.094328 · Cited by 2,580 · see citing works
Experience-dependent structural synaptic plasticity in the mammalian brain
Holtmaat, A., & Svoboda, K. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2699 · Cited by 1,934 · see citing works
MCEWEN, B. S. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1314.001 · Cited by 1,638 · see citing works
The stressed hippocampus, synaptic plasticity and lost memories
Kim, J. J., & Diamond, D. M. (2002) · Nature Reviews Neuroscience · doi:10.1038/nrn849 · Cited by 1,543 · see citing works
Dendritic spine pathology in neuropsychiatric disorders
Penzes, P., Cahill, M. E., Jones, K. A., VanLeeuwen, J.-E., & Woolfrey, K. M. (2011) · Nature Neuroscience · doi:10.1038/nn.2741 · Cited by 1,523 · see citing works
Joëls, M., & Baram, T. Z. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2632 · Cited by 1,521 · see citing works
Self-citationThe stressed synapse: the impact of stress and glucocorticoids on glutamate transmission
Popoli, M., Yan, Z., McEwen, B. S., & Sanacora, G. (2012) · Nature Reviews Neuroscience · doi:10.1038/nrn3138 · Cited by 1,393 · see citing works
Psychobiology and molecular genetics of resilience
Feder, A., Nestler, E. J., & Charney, D. S. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2649 · Cited by 1,272 · see citing works
CRF and CRF receptors: role in stress responsivity and other behaviors
Bale, T. L., & Vale, W. W. (2004) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.44.101802.121410 · Cited by 1,270 · see citing works
Morphological Changes in Dendritic Spines Associated with Long-Term Synaptic Plasticity
Yuste, R., & Bonhoeffer, T. (2001) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.24.1.1071 · Cited by 1,269 · see citing works
Naturally occurring fluctuation in dendritic spine density on adult hippocampal pyramidal neurons
Woolley, C., Gould, E., Frankfurt, M., & McEwen, B. (1990) · Journal of Neuroscience · doi:10.1523/jneurosci.10-12-04035.1990 · Cited by 1,107 · see citing works
Larson, J., Wong, D., & Lynch, G. (1986) · Brain Research · doi:10.1016/0006-8993(86)90579-2 · Cited by 1,037 · see citing works
Self-citationHarris, K., & Kater, S. (1994) · Annual Review of Neuroscience · doi:10.1146/annurev.ne.17.030194.002013 · Cited by 1,032 · see citing works
Recognition memory and the medial temporal lobe: a new perspective
Squire, L. R., Wixted, J. T., & Clark, R. E. (2007) · Nature reviews. Neuroscience · doi:10.1038/nrn2154 · Cited by 1,028 · see citing works
Dentritic spines : structure, dynamics and regulation
Hering, H., & Sheng, M. (2001) · Nature Reviews Neuroscience · doi:10.1038/35104061 · Cited by 961 · see citing works
Balancing Structure and Function at Hippocampal Dendritic Spines
Bourne, J. N., & Harris, K. M. (2008) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.31.060407.125646 · Cited by 916 · see citing works
Molecular mechanisms of dendritic spine morphogenesis
Tada, T., & Sheng, M. (2006) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2005.12.001 · Cited by 615 · see citing works
AMPA Receptor Incorporation into Synapses during LTP: The Role of Lateral Movement and Exocytosis
Makino, H., & Malinow, R. (2009) · Neuron · doi:10.1016/j.neuron.2009.08.035 · Cited by 501 · see citing works
Dendritic spines and long-term plasticity
Segal, M. (2005) · Nature Reviews Neuroscience · doi:10.1038/nrn1649 · Cited by 489 · see citing works
Understanding memory through hippocampal remapping
Colgin, L. L., Moser, E. I., & Moser, M.-B. (2008) · Trends in Neurosciences · doi:10.1016/j.tins.2008.06.008 · Cited by 450 · see citing works
Role of ampa receptor endocytosis in synaptic plasticity
Carroll, R. C., Beattie, E. C., von Zastrow, M., & Malenka, R. C. (2001) · Nature Reviews Neuroscience · doi:10.1038/35072500 · Cited by 448 · see citing works
Neurocognitive Mechanisms in Depression: Implications for Treatment
Clark, L., Chamberlain, S. R., & Sahakian, B. J. (2009) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.31.060407.125618 · Cited by 446 · see citing works
Sánchez, M. M., Young, L. J., Plotsky, P. M., & Insel, T. R. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-12-04657.2000 · Cited by 420 · see citing works
Radulovic, J., Rühmann, A., Liepold, T., & Spiess, J. (1999) · The Journal of Neuroscience · doi:10.1523/jneurosci.19-12-05016.1999 · Cited by 402 · see citing works
Ivy, A. S., Rex, C. S., Chen, Y., Dubé, C., Maras, P. M., Grigoriadis, D. E., Gall, C. M., Lynch, G., & Baram, T. Z. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.1784-10.2010 · Cited by 402 · see citing works
Self-citationBoehm, J., Kang, M.-G., Johnson, R. C., Esteban, J., Huganir, R. L., & Malinow, R. (2006) · Neuron · doi:10.1016/j.neuron.2006.06.013 · Cited by 382 · see citing works
Neural circuits mediating stress
López, J. F., Akil, H., & Watson, S. J. (1999) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00266-8 · Cited by 373 · see citing works
Glucocorticoids are critical regulators of dendritic spine development and plasticity in vivo
Liston, C., & Gan, W.-B. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1110444108 · Cited by 352 · see citing works
Mechanisms for acute stress-induced enhancement of glutamatergic transmission and working memory
Yuen, E. Y., Liu, W., Karatsoreos, I. N., Ren, Y., Feng, J., McEwen, B. S., & Yan, Z. (2011) · Molecular Psychiatry · doi:10.1038/mp.2010.50 · Cited by 324 · see citing works
Distribution of the mineralocorticoid and the glucocorticoid receptor mRNAs in the rat hippocampus
Eekelen, J. A. M. V., Jiang, W., de Kloet, E. R., & Bohn, M. C. (1988) · Journal of Neuroscience Research · doi:10.1002/jnr.490210113 · Cited by 316 · see citing works
Glutamatergic and Dopaminergic Neurons Mediate Anxiogenic and Anxiolytic Effects of CRHR1
Refojo, D., Schweizer, M. C., Kühne, C., Ehrenberg, S., Thoeringer, C. K., Vogl, A. M., Dedic, N., Schumacher, M., von Wolff, G., Avrabos, C., et al. (2011) · Science · doi:10.1126/science.1202107 · Cited by 313 · see citing works
Diffusional trapping of GluR1 AMPA receptors by input-specific synaptic activity
Ehlers, M. D., Heine, M., Groc, L., Lee, M.-C., & Choquet, D. (2007) · Neuron · doi:10.1016/j.neuron.2007.04.010 · Cited by 300 · see citing works
Changes in Synaptic Morphology Accompany Actin Signaling during LTP
Chen, L. Y., Rex, C. S., Casale, M. S., Gall, C. M., & Lynch, G. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.0164-07.2007 · Cited by 296 · see citing works
Self-citationRex, C. S., Chen, L. Y., Sharma, A., Liu, J., Babayan, A. H., Gall, C. M., & Lynch, G. (2009) · Journal of Cell Biology · doi:10.1083/jcb.200901084 · Cited by 293 · see citing works
Self-citationChen, Y., Dubé, C. M., Rice, C. J., & Baram, T. Z. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.0225-08.2008 · Cited by 276 · see citing works
Self-citationCytoskeletal changes underlie estrogen’s acute effects on synaptic transmission and plasticity.
Kramár, E. A., Chen, L. Y., Brandon, N. J., Rex, C. S., Liu, F., Gall, C. M., & Lynch, G. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.3059-09.2009 · Cited by 264 · see citing works
Self-citationRoozendaal, B., Brunson, K. L., Holloway, B. L., McGaugh, J. L., & Baram, T. Z. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.212504599 · Cited by 258 · see citing works
Self-citationChen, Y., Rex, C. S., Rice, C. J., Dubé, C. M., Gall, C. M., Lynch, G., & Baram, T. Z. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1003825107 · Cited by 256 · see citing works
Self-citationBehan, D., Heinrichs, S., Troncoso, J., Liu, X.-J., Kawas, C., Ling, N., & de Souza, E. D. (1995) · Nature · doi:10.1038/378284a0 · Cited by 248 · see citing works
Repeated stress and structural plasticity in the brain
Radley, J. J., & Morrison, J. H. (2005) · Ageing Research Reviews · doi:10.1016/j.arr.2005.03.004 · Cited by 241 · see citing works
Diamond, D. M., Campbell, A. M., Park, C. R., Woodson, J. C., Conrad, C. D., Bachstetter, A. D., & Mervis, R. F. (2006) · Hippocampus · doi:10.1002/hipo.20188 · Cited by 213 · see citing works
Blank, T., Nijholt, I. M., Eckart, K., & Spiess, J. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-09-03788.2002 · Cited by 210 · see citing works
Stress hormones and AMPA receptor trafficking in synaptic plasticity and memory
Krugers, H. J., Hoogenraad, C. C., & Groc, L. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2913 · Cited by 197 · see citing works
Theta Stimulation Polymerizes Actin in Dendritic Spines of Hippocampus
Lin, B., Kramár, E. A., Bi, X., Brücher, F., Gall, C. M., & LYNCH, G. S. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.4283-04.2005 · Cited by 180 · see citing works
Self-citationHippocampal corticotropin releasing hormone: pre- and postsynaptic location and release by stress
Chen, Y., Brunson, K. L., Adelmann, G., Bender, R. A., Frotscher, M., & Baram, T. Z. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2004.03.036 · Cited by 179 · see citing works
Self-citationActin and the agile spine: How and why do dendritic spines dance?
Halpain, S. (2000) · Trends in Neurosciences · doi:10.1016/s0166-2236(00)01576-9 · Cited by 169 · see citing works
Contextual learning requires synaptic AMPA receptor delivery in the hippocampus
Mitsushima, D., Ishihara, K., Sano, A., Kessels, H. W. H. G., & Takahashi, T. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1104558108 · Cited by 163 · see citing works
Dendritic spine dynamics--a key role for kalirin-7
Penzes, P., & Jones, K. A. (2008) · Trends in Neurosciences · doi:10.1016/j.tins.2008.06.001 · Cited by 157 · see citing works
Wang, X., Chen, Y., Wolf, M., Wagner, K. V., Liebl, C., Scharf, S. H., Harbich, D., Mayer, B., Wurst, W., Holsboer, F., et al. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.01.020 · Cited by 157 · see citing works
Self-citationChronic Stress- and Sex-Specific Neuromorphological and Functional Changes in Limbic Structures
McLaughlin, K. J., Baran, S. E., & Conrad, C. D. (2009) · Molecular Neurobiology · doi:10.1007/s12035-009-8079-7 · Cited by 152 · see citing works
Evidence That Long-Term Potentiation Occurs within Individual Hippocampal Synapses during Learning
Fedulov, V., Rex, C. S., Simmons, D. A., Palmer, L. C., Gall, C. M., & LYNCH, G. S. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.2003-07.2007 · Cited by 150 · see citing works
Self-citationStress‐induced dynamic routing of hippocampal connectivity: A hypothesis
Segal, M., Richter‐Levin, G., & Maggio, N. (2010) · Hippocampus · doi:10.1002/hipo.20751 · Cited by 146 · see citing works
Ryan, X. P., Alldritt, J., Svenningsson, P., Allen, P. B., Wu, G.-Y., Nairn, A. C., & Greengard, P. (2005) · Neuron · doi:10.1016/j.neuron.2005.05.013 · Cited by 142 · see citing works
Chen, Y., Bender, R. A., Frotscher, M., & Baram, T. Z. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-18-07171.2001 · Cited by 137 · see citing works
Self-citationRemodeling of neuronal networks by stress
Fuchs, E. (2006) · Frontiers in bioscience · doi:10.2741/2004 · Cited by 127 · see citing works
Sfakianos, M. K., Eisman, A. S., Gourley, S. L., Bradley, W. D., Scheetz, A. J., Settleman, J. E., Taylor, J. R., Greer, C. A., Williamson, A., & Koleske, A. J. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.0793-07.2007 · Cited by 126 · see citing works
Learning rules and persistence of dendritic spines
Kasai, H., Hayama, T., Ishikawa, M., Watanabe, S., Yagishita, S., & Noguchi, J. (2010) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2010.07344.x · Cited by 118 · see citing works
Stress and the Developing Hippocampus: A Double-Edged Sword?
Brunson, K. L., Chen, Y., Avishai‐Eliner, S., & Baram, T. Z. (2003) · Molecular Neurobiology · doi:10.1385/mn:27:2:121 · Cited by 86 · see citing works
Self-citationKang, M.-G., Guo, Y., & Huganir, R. L. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0812861106 · Cited by 82 · see citing works
Noam, Y., Zha, Q., Phan, L., Wu, R.-L., Chetkovich, D. M., Wadman, W. J., & Baram, T. Z. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.070391 · Cited by 66 · see citing works
Self-citationSchmidt, M. V., Schülke, J.-P., Liebl, C., Stieß, M., Avrabos, C., Bock, J., Wochnik, G. M., Davies, H. A., Zimmermann, N., Scharf, S. H., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1103318108 · Cited by 64 · see citing works
Khan, S. A., Milot, M. R., Lecompte-Collin, J., & Plamondon, H. (2004) · Brain Research · doi:10.1016/j.brainres.2004.04.062 · Cited by 28 · see citing works
Effects of olanzapine and quetiapine on corticotropin-releasing hormone release in the rat brain
Tringali, G., Lisi, L., Simone, M. L. D., Aubry, J., Preziosi, P., Pozzoli, G., & Navarra, P. (2009) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2009.05.012 · Cited by 16 · see citing works
Advances in depression research: 2011
Licinio, J., & Wong, M. (2011) · Molecular Psychiatry · doi:10.1038/mp.2011.74 · Cited by 15 · see citing works
Episodic memory, semantic memory, and amnesia
Squire, L. R., & Zola, S. M. (1998) · Hippocampus · doi:10.1002/(sici)1098-1063(1998)8:3
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- Authors
- Chen, Y., Kramár, E. A., Chen, L. Y., Babayan, A. H., Andres, A. L., Gall, C. M., Lynch, G., & Baram, T. Z.
- Affiliations
- University of California, Irvine (US)
- Corresponding author
- Chen, Y
- Baram, T Z
- Venue
- Molecular Psychiatry
- Published
- 2012-03-13
- Volume
- 18
- Issue
- 4
- Pages
- 485-496
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC3440527
- OpenAlex
- W2088857895
- Cited by
- 115
- References
- 68
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 7 · 2023: 2 · 2022: 8 · 2021: 6 · 2020: 4 · 2019: 12 · 2018: 14 · 2017: 11 · 2016: 11 · 2015: 9 · 2014: 7 · 2013: 10 · 2012: 5
- FWCI
- 4.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- National Institutes of Health
- National Institute of Mental Health (MH083396, MH73136, F31MH083396, R01MH073136)
- National Institute of Neurological Disorders and Stroke (P01NS045260, NS 28912, R01NS028912, P01 NS45260)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- corticotropin-releasing factor, chronic stress, dendritic spines, synaptic plasticity, RhoA signaling, actin polymerization, hippocampus, synaptic transmission, memory impairment, excitatory synapses
- MeSH terms
- Actins, Animals, Corticotropin-Releasing Hormone, Hippocampus, Humans, Male, Synaptic Transmission, Neuronal Plasticity, Synapses, Signal Transduction, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, Excitatory Postsynaptic Potentials, rhoA GTP-Binding Protein, Protein Kinase Inhibitors, Dendritic Spines, Mice, Rats
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