Perineuronal nets (PNNs) enwrap mature neurons, playing a role in the control of plasticity and synapse dynamics. PNNs have been shown to have effects on memory formation, retention and extinction in a variety of animal models. It has been proposed that the cavities in PNNs, which contain synapses, can act as a memory store and that they remain stable after events that cause synaptic withdrawal such as anoxia or hibernation. We examine this idea by monitoring place memory before and after synaptic withdrawal caused by acute hibernation-like state (HLS). Animals lacking hippocampal PNNs due to enzymatic digestion by chondroitinase ABC or knockout of the PNN component aggrecan were compared with wild type controls. HLS-induced synapse withdrawal caused a memory deficit, but not to the level of untreated naïve animals and not worsened by PNN attenuation. After HLS, only animals lacking PNNs showed memory restoration or relearning. Absence of PNNs affected the restoration of excitatory synapses on PNN-bearing neurons. The results support a role for hippocampal PNNs in learning, but not in long-term memory storage for correction of deficits.

Faculty of Biological Sciences University of Leeds Leeds UK

Imaging Methods Core Facility BIOCEV CAS Vestec Czech Republic

Institute of Experimental Medicine CAS Prague Czech Republic

John van Geest Centre for Brain Repair University of Cambridge Cambridge UK

UK Dementia Research Institute and Department of Clinical Neurosciences University of Cambridge Cambridge UK

Zobrazit více v PubMed

Arnst N, Kuznetsova S, Lipachev N, Shaikhutdinov N, Melnikova A, Mavlikeev M, et al. Spatial patterns and cell surface clusters in perineuronal nets. Brain Res. 2016;1648:214–23. PubMed

Frischknecht R, Heine M, Perrais D, Seidenbecher CI, Choquet D, Gundelfinger ED. Brain extracellular matrix affects AMPA receptor lateral mobility and short-term synaptic plasticity. Nat Neurosci. 2009;12:897–904. PubMed

Deepa SS, Carulli D, Galtrey C, Rhodes K, Fukuda J, Mikami T, et al. Composition of perineuronal net extracellular matrix in rat brain: a different disaccharide composition for the net-associated proteoglycans. J Biol Chem. 2006;281:17789–800. PubMed

Irvine SF, Kwok JCF. Perineuronal nets in spinal motoneurones: chondroitin sulphate proteoglycan around alpha motoneurones. Int J Mol Sci. 2018;19:1172. PubMed PMC

Lensjo KK, Christensen AC, Tennoe S, Fyhn M, Hafting T. Differential expression and cell-type specificity of perineuronal nets in hippocampus, medial entorhinal cortex, and visual cortex examined in the rat and mouse. eNeuro. 2017;4:ENEURO.0379-16.2017. PubMed PMC

Ueno H, Suemitsu S, Murakami S, Kitamura N, Wani K, Matsumoto Y, et al. Layer-specific expression of extracellular matrix molecules in the mouse somatosensory and piriform cortices. IBRO Rep. 2019;6:1–17. PubMed PMC

Jager C, Lendvai D, Seeger G, Bruckner G, Matthews RT, Arendt T, et al. Perineuronal and perisynaptic extracellular matrix in the human spinal cord. Neuroscience. 2013;238:168–84. PubMed

Fawcett JW, Oohashi T, Pizzorusso T. The roles of perineuronal nets and the perinodal extracellular matrix in neuronal function. Nat Rev Neurosci. 2019;20:451–65. PubMed

Beurdeley M, Spatazza J, Lee HH, Sugiyama S, Bernard C, Di Nardo AA, et al. Otx2 binding to perineuronal nets persistently regulates plasticity in the mature visual cortex. J Neurosci. 2012;32:9429–37. PubMed PMC

Hou X, Yoshioka N, Tsukano H, Sakai A, Miyata S, Watanabe Y, et al. Chondroitin sulfate is required for onset and offset of critical period plasticity in visual cortex. Sci Rep. 2017;7:12646. PubMed PMC

Reichelt AC, Hare DJ, Bussey TJ, Saksida LM. Perineuronal nets: plasticity, protection, and therapeutic potential. Trends Neurosci. 2019;42:458–70. PubMed

Gottschling C, Wegrzyn D, Denecke B, Faissner A. Elimination of the four extracellular matrix molecules tenascin-C, tenascin-R, brevican and neurocan alters the ratio of excitatory and inhibitory synapses. Sci Rep. 2019;9:13939. PubMed PMC

Saroja SR, Sase A, Kircher SG, Wan J, Berger J, Hoger H, et al. Hippocampal proteoglycans brevican and versican are linked to spatial memory of Sprague-Dawley rats in the morris water maze. J Neurochem. 2014;130:797–804. PubMed

Wiera G, Mozrzymas JW. Extracellular proteolysis in structural and functional plasticity of mossy fiber synapses in hippocampus. Front Cell Neurosci. 2015;9:427. PubMed PMC

Carulli D, Verhaagen J. An extracellular perspective on CNS maturation: perineuronal nets and the control of plasticity. Int J Mol Sci. 2021;22:2434. PubMed PMC

Fawcett JW, Fyhn M, Jendelova P, Kwok JCF, Ruzicka J, Sorg BA. The extracellular matrix and perineuronal nets in memory. Mol Psychiatry. 2022 10.1038/s41380-022-01634-3. PubMed PMC

Gogolla N, Caroni P, Luthi A, Herry C. Perineuronal nets protect fear memories from erasure. Science. 2009;325:1258–61. PubMed

Yang S, Cacquevel M, Saksida LM, Bussey TJ, Schneider BL, Aebischer P, et al. Perineuronal net digestion with chondroitinase restores memory in mice with tau pathology. Exp Neurol. 2015;265:48–58. PubMed PMC

Romberg C, Yang S, Melani R, Andrews MR, Horner AE, Spillantini MG, et al. Depletion of perineuronal nets enhances recognition memory and long-term depression in the perirhinal cortex. J Neurosci. 2013;33:7057–65. PubMed PMC

Yang S, Gigout S, Molinaro A, Naito-Matsui Y, Hilton S, Foscarin S, et al. Chondroitin 6-sulphate is required for neuroplasticity and memory in ageing. Mol Psychiatry. 2021;26:5658–68. PubMed PMC

Carulli D, Broersen R, de Winter F, Muir EM, Meskovic M, de Waal M, et al. Cerebellar plasticity and associative memories are controlled by perineuronal nets. Proc Natl Acad Sci USA. 2020;117:6855–65. PubMed PMC

Slaker M, Churchill L, Todd RP, Blacktop JM, Zuloaga DG, Raber J, et al. Removal of perineuronal nets in the medial prefrontal cortex impairs the acquisition and reconsolidation of a cocaine-induced conditioned place preference memory. J Neurosci. 2015;35:4190–202. PubMed PMC

Blacktop JM, Sorg BA. Perineuronal nets in the lateral hypothalamus area regulate cue-induced reinstatement of cocaine-seeking behavior. Neuropsychopharmacology. 2019;44:850–8. PubMed PMC

Blacktop JM, Todd RP, Sorg BA. Role of perineuronal nets in the anterior dorsal lateral hypothalamic area in the acquisition of cocaine-induced conditioned place preference and self-administration. Neuropharmacology. 2017;118:124–36. PubMed PMC

Slaker ML, Jorgensen ET, Hegarty DM, Liu X, Kong Y, Zhang F, et al. Cocaine exposure modulates perineuronal nets and synaptic excitability of fast-spiking interneurons in the medial prefrontal cortex. eNeuro. 2018;5:ENEURO.0221–18.2018. PubMed PMC

Xue YX, Xue LF, Liu JF, He J, Deng JH, Sun SC, et al. Depletion of perineuronal nets in the amygdala to enhance the erasure of drug memories. J Neurosci. 2014;34:6647–58. PubMed PMC

Tsien RY. Very long-term memories may be stored in the pattern of holes in the perineuronal net. Proc Natl Acad Sci USA. 2013;110:12456–61. PubMed PMC

Marchand A, Schwartz C. Perineuronal net expression in the brain of a hibernating mammal. Brain Struct Funct. 2020;225:45–56. PubMed

Hobohm C, Gunther A, Grosche J, Rossner S, Schneider D, Bruckner G. Decomposition and long-lasting downregulation of extracellular matrix in perineuronal nets induced by focal cerebral ischemia in rats. J Neurosci Res. 2005;80:539–48. PubMed

Arendt T, Bullmann T. Neuronal plasticity in hibernation and the proposed role of the microtubule-associated protein tau as a “master switch” regulating synaptic gain in neuronal networks. Am J Physiol Regul Integr Comp Physiol. 2013;305:R478–89. PubMed

le Feber J, Erkamp N, van Putten M, Hofmeijer J. Loss and recovery of functional connectivity in cultured cortical networks exposed to hypoxia. J Neurophysiol. 2017;118:394–403. PubMed PMC

Sandvig I, Augestad IL, Haberg AK, Sandvig A. Neuroplasticity in stroke recovery. The role of microglia in engaging and modifying synapses and networks. Eur J Neurosci. 2018;47:1414–28. PubMed

Xerri C, Zennou-Azogui Y, Sadlaoud K, Sauvajon D. Interplay between intra- and interhemispheric remodeling of neural networks as a substrate of functional recovery after stroke: adaptive versus maladaptive reorganization. Neuroscience. 2014;283:178–201. PubMed

Carlin JL, Jain S, Duroux R, Suresh RR, Xiao C, Auchampach JA, et al. Activation of adenosine A2A or A2B receptors causes hypothermia in mice. Neuropharmacology. 2018;139:268–78. PubMed PMC

Carlin JL, Jain S, Gizewski E, Wan TC, Tosh DK, Xiao C, et al. Hypothermia in mouse is caused by adenosine A1 and A3 receptor agonists and AMP via three distinct mechanisms. Neuropharmacology. 2017;114:101–13. PubMed PMC

Carlin JL, Tosh DK, Xiao C, Pinol RA, Chen Z, Salvemini D, et al. Peripheral adenosine A3 receptor activation causes regulated hypothermia in mice that is dependent on central histamine H1 Receptors. J Pharmacol Exp Ther. 2016;356:474–82. PubMed PMC

Kawamura M, Jr., Ruskin DN, Masino SA. Adenosine A1 receptor-mediated protection of mouse hippocampal synaptic transmission against oxygen and/or glucose deprivation: a comparative study. J Neurophysiol. 2019;122:721–8. PubMed PMC

Bastide A, Peretti D, Knight JR, Grosso S, Spriggs RV, Pichon X, et al. RTN3 is a novel cold-induced protein and mediates neuroprotective effects of RBM3. Curr Biol. 2017;27:638–50. PubMed PMC

Peretti D, Bastide A, Radford H, Verity N, Molloy C, Martin MG, et al. RBM3 mediates structural plasticity and protective effects of cooling in neurodegeneration. Nature. 2015;518:236–9. PubMed PMC

Broadbent NJ, Squire LR, Clark RE. Reversible hippocampal lesions disrupt water maze performance during both recent and remote memory tests. Learn Mem. 2006;13:187–91. PubMed PMC

Kentros C, Hargreaves E, Hawkins RD, Kandel ER, Shapiro M, Muller RV. Abolition of long-term stability of new hippocampal place cell maps by NMDA receptor blockade. Science. 1998;280:2121–6. PubMed

Morris RG, Garrud P, Rawlins JN, O’Keefe J. Place navigation impaired in rats with hippocampal lesions. Nature. 1982;297:681–3. PubMed

O’Keefe J. A review of the hippocampal place cells. Prog Neurobiol. 1979;13:419–39. PubMed

Tanaka KZ, He H, Tomar A, Niisato K, Huang AJY, McHugh TJ. The hippocampal engram maps experience but not place. Science. 2018;361:392–7. PubMed

Lensjo KK, Lepperod ME, Dick G, Hafting T, Fyhn M. Removal of perineuronal nets unlocks juvenile plasticity through network mechanisms of decreased inhibition and increased gamma activity. J Neurosci. 2017;37:1269–83. PubMed PMC

Lin R, Kwok JC, Crespo D, Fawcett JW, Chondroitinase ABC. has a long lasting effect on chondroitin sulphate glycosaminoglycan content in the injured rat brain. J Neurochem. 2008;104:400–8. PubMed

Donato F, Chowdhury A, Lahr M, Caroni P. Early- and late-born parvalbumin basket cell subpopulations exhibiting distinct regulation and roles in learning. Neuron. 2015;85:770–86. PubMed

Morellini F, Sivukhina E, Stoenica L, Oulianova E, Bukalo O, Jakovcevski I, et al. Improved reversal learning and working memory and enhanced reactivity to novelty in mice with enhanced GABAergic innervation in the dentate gyrus. Cereb Cortex. 2010;20:2712–27. PubMed

Rowlands D, Lensjo KK, Dinh T, Yang S, Andrews MR, Hafting T, et al. Aggrecan directs extracellular matrix-mediated neuronal plasticity. J Neurosci. 2018;38:10102–13. PubMed PMC

O’Mara SM, Aggleton JP. Space and memory (far) beyond the hippocampus: many subcortical structures also support cognitive mapping and mnemonic processing. Front Neural Circuits. 2019;13:52. PubMed PMC

Nelson AJ, Hindley EL, Pearce JM, Vann SD, Aggleton JP. The effect of retrosplenial cortex lesions in rats on incidental and active spatial learning. Front Behav Neurosci. 2015;9:11. PubMed PMC

Steullet P, Cabungcal JH, Cuenod M, Do KQ. Fast oscillatory activity in the anterior cingulate cortex: dopaminergic modulation and effect of perineuronal net loss. Front Cell Neurosci. 2014;8:244. PubMed PMC

Christensen AC, Lensjo KK, lepperod ME, Dragly S-A, Sutterud H, Blackstad JS, et al. Perineuronal nets stabilize the grid cell network. BioRxiv. 2020. PubMed PMC

Bertocchi I, Mele P, Ferrero G, Oberto A, Carulli D, Eva C. NPY-Y1 receptor signaling controls spatial learning and perineuronal net expression. Neuropharmacology. 2020;184:108425. PubMed

Khoo GH, Lin YT, Tsai TC, Hsu KS. Perineuronal nets restrict the induction of long-term depression in the mouse hippocampal CA1 region. Mol Neurobiol. 2019;56:6436–50. PubMed

Bukalo O, Schachner M, Dityatev A. Modification of extracellular matrix by enzymatic removal of chondroitin sulfate and by lack of tenascin-R differentially affects several forms of synaptic plasticity in the hippocampus. Neuroscience. 2001;104:359–69. PubMed

Hayani H, Song I, Dityatev A. Increased excitability and reduced excitatory synaptic input into fast-spiking CA2 interneurons after enzymatic attenuation of extracellular matrix. Front Cell Neurosci. 2018;12:149. PubMed PMC

Carstens KE, Phillips ML, Pozzo-Miller L, Weinberg RJ, Dudek SM. Perineuronal nets suppress plasticity of excitatory synapses on CA2 pyramidal neurons. J Neurosci. 2016;36:6312–20. PubMed PMC

Fawcett JW, Kwok JCF. Proteoglycan sulphation in the function of the mature central nervous system. Front Integr Neurosci. 2022;16:895493. PubMed PMC

Morawski M, Bruckner G, Arendt T, Matthews RT. Aggrecan: beyond cartilage and into the brain. Int J Biochem Cell Biol. 2012;44:690–3. PubMed

Happel MF, Niekisch H, Castiblanco Rivera LL, Ohl FW, Deliano M, Frischknecht R. Enhanced cognitive flexibility in reversal learning induced by removal of the extracellular matrix in auditory cortex. Proc Natl Acad Sci USA. 2014;111:2800–5. PubMed PMC

Thompson EH, Lensjo KK, Wigestrand MB, Malthe-Sorenssen A, Hafting T, Fyhn M. Removal of perineuronal nets disrupts recall of a remote fear memory. Proc Natl Acad Sci USA. 2018;115:607–12. PubMed PMC

Hylin MJ, Orsi SA, Moore AN, Dash PK. Disruption of the perineuronal net in the hippocampus or medial prefrontal cortex impairs fear conditioning. Learn Mem. 2013;20:267–73. PubMed PMC

Shi W, Wei X, Wang X, Du S, Liu W, Song J, et al. Perineuronal nets protect long-term memory by limiting activity-dependent inhibition from parvalbumin interneurons. Proc Natl Acad Sci USA. 2019;116:27063–73. PubMed PMC

Vegh MJ, Heldring CM, Kamphuis W, Hijazi S, Timmerman AJ, Li KW, et al. Reducing hippocampal extracellular matrix reverses early memory deficits in a mouse model of Alzheimer’s disease. Acta Neuropathol Commun. 2014;2:76. PubMed PMC

Yang S, Hilton S, Alves JN, Saksida LM, Bussey T, Matthews RT, et al. Antibody recognizing 4-sulfated chondroitin sulfate proteoglycans restores memory in tauopathy-induced neurodegeneration. Neurobiol Aging. 2017;59:197–209. PubMed

Sorg BA, Berretta S, Blacktop JM, Fawcett JW, Kitagawa H, Kwok JC, et al. Casting a wide net: role of perineuronal nets in neural plasticity. J Neurosci. 2016;36:11459–68. PubMed PMC

Pantazopoulos H, Berretta S. In sickness and in health: perineuronal nets and synaptic plasticity in psychiatric disorders. Neural Plast. 2016;2016:9847696. PubMed PMC

Testa D, Prochiantz A, Di Nardo AA. Perineuronal nets in brain physiology and disease. Semin Cell Dev Biol. 2019;89:125–35. PubMed

Wen TH, Binder DK, Ethell IM, Razak KA. The perineuronal ‘Safety’ net? Perineuronal net abnormalities in neurological disorders. Front Mol Neurosci. 2018;11:270. PubMed PMC

Pantazopoulos H, Markota M, Jaquet F, Ghosh D, Wallin A, Santos A, et al. Aggrecan and chondroitin-6-sulfate abnormalities in schizophrenia and bipolar disorder: a postmortem study on the amygdala. Transl Psychiatry. 2015;5:e496. PubMed PMC

The extracellular matrix and perineuronal nets in memory

Proteoglycan Sulphation in the Function of the Mature Central Nervous System