It is one of the major challenges in the field of Neuroscience to unravel the molecular and physiological mechanisms underlying memory formation and related diseases. The group of De Zeeuw aims to tackle this central theme by investigating plasticity and dynamics of sensorimotor systems that control readily tractable motor behaviours. Three lines of objectives and research can be distinguished:
- to elucidate the role of the vestibulocerebellum in the performance and adaptation of compensatory eye movements;
- to elucidate the role of the olivocerebellar system in eyelid conditioning; and
- to elucidate the functional interactions between the cerebellum and cerebral cortex during adaptation to perturbations in locomotion.
All specific aims are investigated by creating cell specific mouse mutants and by analyzing them at the molecular, cellular and systems physiological, as well as behavioural level. Subsequently, the outcomes of the investigations in mouse models are verified by examining patients with related diseases, and if possible, new designs for therapies are developed based on the mechanisms discovered in the animal models.
Selected recent publications
De Zeeuw CI, Hoebeek FE, Bosman LW, Schonewille M, Witter L, Koekkoek SK. Spatiotemporal firing patterns in the cerebellum. Nat Rev Neurosci. 2011 Jun;12(6):327-44. Epub 2011 May 5. PubMed PMID: 21544091.
Schonewille M, Gao Z, Boele HJ, Veloz MF, Amerika WE, Simek AA, De Jeu MT, Steinberg JP, Takamiya K, Hoebeek FE, Linden DJ, Huganir RL, De Zeeuw CI. Reevaluating the role of LTD in cerebellar motor learning. Neuron. 2011 Apr 14;70(1):43-50. PubMed PMID: 21482355; PubMed Central PMCID: PMC3104468.
Andreescu CE, Prestori F, Brandalise F, D’Errico A, De Jeu MT, Rossi P, Botta L, Kohr G, Perin P, D’Angelo E, De Zeeuw CI. NR2A subunit of the N-methyl D-aspartate receptors are required for potentiation at the mossy fiber to granule cell synapse and vestibulo-cerebellar motor learning. Neuroscience. 2011 Mar 10;176:274-83. Epub 2010 Dec 23. PubMed PMID: 21185357.
Smit A, van der Geest J, Metselaar M, van der Lugt A, VanderWerf F, De Zeeuw C. Long-term changes in cerebellar activation during functional recovery from transient peripheral motor paralysis. Exp Neurol. 2010 Nov;226(1):33-9. Epub 2010 Aug 5. PubMed PMID: 20691681.
Belmeguenai A, Hosy E, Bengtsson F, Pedroarena CM, Piochon C, Teuling E, He Q, Ohtsuki G, De Jeu MT, Elgersma Y, De Zeeuw CI, Jörntell H, Hansel C. Intrinsic plasticity complements long-term potentiation in parallel fiber input gain control in cerebellar Purkinje cells. J Neurosci. 2010 Oct 13;30(41):13630-43. PubMed PMID: 20943904; PubMed Central PMCID: PMC2968711.
Bosman LW, Koekkoek SK, Shapiro J, Rijken BF, Zandstra F, van der Ende B, Owens CB, Potters JW, de Gruijl JR, Ruigrok TJ, De Zeeuw CI. Encoding of whisker input by cerebellar Purkinje cells. J Physiol. 2010 Oct 1;588(Pt 19):3757-83. PubMed PMID: 20724365; PubMed Central PMCID: PMC2998225.
Voogd J, Schraa-Tam CK, van der Geest JN, De Zeeuw CI. Visuomotor Cerebellum in Human and Nonhuman Primates. Cerebellum. 2010 Aug 31. [Epub ahead of print] PubMed PMID: 20809106.
Schonewille M, Belmeguenai A, Koekkoek SK, Houtman SH, Boele HJ, van Beugen BJ, Gao Z, Badura A, Ohtsuki G, Amerika WE, Hosy E, Hoebeek FE, Elgersma Y, Hansel C, De Zeeuw CI. Purkinje cell-specific knockout of the protein phosphatase PP2B impairs potentiation and cerebellar motor learning. Neuron. 2010 Aug 26;67(4):618-28. PubMed PMID: 20797538; PubMed Central PMCID: PMC2941980.
Hoebeek FE, Witter L, Ruigrok TJ, De Zeeuw CI. Differential olivo-cerebellar cortical control of rebound activity in the cerebellar nuclei. Proc Natl Acad Sci U S A. 2010 May 4;107(18):8410-5. Epub 2010 Apr 15. PubMed PMID: 20395550; PubMed Central PMCID: PMC2889566.
D’Angelo E, Koekkoek SK, Lombardo P, Solinas S, Ros E, Garrido J, Schonewille M, De Zeeuw CI. Timing in the cerebellum: oscillations and resonance in the granular layer. Neuroscience. 2009 Sep 1;162(3):805-15. Epub 2009 Jan 31. PubMed PMID: 19409229.
Wulff P, Schonewille M, Renzi M, Viltono L, Sassoè-Pognetto M, Badura A, Gao Z, Hoebeek FE, van Dorp S, Wisden W, Farrant M, De Zeeuw CI. Synaptic inhibition of Purkinje cells mediates consolidation of vestibulo-cerebellar motor learning. Nat Neurosci. 2009 Aug;12(8):1042-9. Epub 2009 Jul 5. PubMed PMID: 19578381; PubMed Central PMCID: PMC2718327.
van Woerden GM, Hoebeek FE, Gao Z, Nagaraja RY, Hoogenraad CC, Kushner SA, Hansel C, De Zeeuw CI, Elgersma Y. betaCaMKII controls the direction of plasticity at parallel fiber-Purkinje cell synapses. Nat Neurosci. 2009 Jul;12(7):823-5. Epub 2009 Jun 7. PubMed PMID: 19503086.
D’Angelo E, De Zeeuw CI. Timing and plasticity in the cerebellum: focus on the granular layer. Trends Neurosci. 2009 Jan;32(1):30-40. Epub 2008 Oct 30. Review. PubMed PMID: 18977038.
Belmeguenai A, Botta P, Weber JT, Carta M, De Ruiter M, De Zeeuw CI, Valenzuela CF, Hansel C. Alcohol impairs long-term depression at the cerebellar parallel fiber-Purkinje cell synapse. J Neurophysiol. 2008 Dec;100(6):3167-74. Epub 2008 Oct 15. PubMed PMID: 18922952; PubMed Central PMCID: PMC2604851.
De Zeeuw CI, Hoebeek FE, Schonewille M. Causes and consequences of oscillations in the cerebellar cortex. Neuron. 2008 Jun 12;58(5):655-8. PubMed PMID: 18549777.
Van Der Giessen RS, Koekkoek SK, van Dorp S, De Gruijl JR, Cupido A, Khosrovani S, Dortland B, Wellershaus K, Degen J, Deuchars J, Fuchs EC, Monyer H, Willecke K, De Jeu MT, De Zeeuw CI. Role of olivary electrical coupling in cerebellar motor learning. Neuron. 2008 May 22;58(4):599-612. PubMed PMID: 18498740.
Jaarsma D, Teuling E, Haasdijk ED, De Zeeuw CI, Hoogenraad CC. Neuron-specific expression of mutant superoxide dismutase is sufficient to induce amyotrophic lateral sclerosis in transgenic mice. J Neurosci. 2008 Feb 27;28(9):2075-88. PubMed PMID: 18305242.
Hoebeek FE, Khosrovani S, Witter L, De Zeeuw CI. Purkinje cell input to cerebellar nuclei in tottering: ultrastructure and physiology. Cerebellum. 2008;7(4):547-58. Epub 2008 Dec 11. PubMed PMID: 19082682.
· Andreescu CE, Milojkovic BA, Haasdijk ED, Kramer P, De Jong FH, Krust A, De Zeeuw CI, De Jeu MT. Estradiol improves cerebellar memory formation by activating estrogen receptor beta. J Neurosci 2007;27(40):10832-10839 (pubmed)
· Khosrovani S, Van Der Giessen RS, De Zeeuw CI, De Jeu MT. In vivo mouse inferior olive neurons exhibit heterogeneous subthreshold oscillations and spiking patterns. Proc Natl Acad Sci USA 2007;104(40):15911-15916 (pubmed)
· Steuber V, Mittmann W, Hoebeek FE, Silver RA, De Zeeuw CI, Häusser M, De Schutter E. Cerebellar LTD and pattern recognition by Purkinje cells: computer simulations and experiments. Neuron 2007;54(1):121-136 (pubmed)
· Schonewille M, Khosrovani S, Winkelman B, Hoebeek FE, De Jeu MTG, Larsen IM, Van der Burg J, Schmolesky MT, Frens MA, De Zeeuw CI. Purkinje cells in awake behaving animals operate at the upstate membrane potential. Nat Neurosci 2006;9:459-461 (pubmed)
· Schonewille M, Khosrovani S, Winkelman BH, Hoebeek FE, De Jeu MT, Larsen IM, Van Hansel C, De Jeu MT, Belmeguenai A, Houtman SH, Buitendijk G, Andreev D, De Zeeuw CI, Elgersma Y. CaMKII is essential for cerebellar LTD and motor learning. Neuron 2006;51(6):835-843 (pubmed)
· Burguière E, Arleo A, Hojjati YM, Elgersma Y, De Zeeuw CI, Berthoz A, Rondi-Reig L. Spatial navigation impairment in mice lacking cerebellar LTD: a motor adaptation deficit rather than a localization problem. Nature Neuroscience 2005;10:1292-1294 (pubmed)
· Hoebeek FE, Stahl JS, Van Alphen AM, Schonewille M, Luo C, Rutteman M, Van den Maagdenberg AMJM, Molenaar PC, Goossens HHLM, Frens MA, De Zeeuw CI. Increased noise level of Purkinje cell activities minimizes impact of their modulation during sensorimotor control. Neuron 2005;45:953-965 (pubmed)
· Koekkoek SK, Yamaguchi K, Milojkovic BA, Dortland BR, Ruigrok TJH, Maex R, Vellema M, Smit AE, Van der Werf F, Bakker CE, Willemsen R, Ikeda T, Kakizawa S, Onodera K, Nelson DL, Mientjes E, Joosten M, De Schutter E, Oostra BA, Ito M, De Zeeuw CI. Deletion of FMR1 in Purkinje cells enhances parallel fiber LTD, enlarges spines, and attenuates eyelid conditioning in a manner which phenocopies human Fragile X syndrome. Neuron 2005;47:339-352 (pubmed)
· De Zeeuw CI, Yeo CH. Time and tide in cerebellar memory formation. Curr Opin Neurobiol 2005;15(6):667-674 (pubmed)
· Coesmans M, Weber JT, De Zeeuw CI, Hansel C. Bidirectional parallel fiber plasticity in the cerebellum under climbing fiber control. Neuron 2004;44:691-700 (pubmed)
· Coesmans M, Sillevis Smitt PA, Linden DJ, Shigemoto R, Hirano T, Yamakawa Y, van Alphen AM, Luo C, van der Geest JN, Gaillard CA, Frens MA, and de Zeeuw CI. Mechanisms underlying deficits in cerebellar motor coordination due to auto-antibodies against mGluR1. Annals of Neurology 2003;53:325-336 (pubmed)
· Koekkoek SK, Hulscher HC, Dortland BR, Hensbroek RA, Elgersma Y, Ruigrok TJ, De Zeeuw CI. Cerebellar LTD and learning-dependent timing of conditioned eyelid responses. Science 2003;301:1736-1739 (pubmed)
· De Zeeuw CI, Chorev E, Devor A, Manor Y, Van Der Giessen RS, De Jeu MT, Hoogenraad CC, Bijman J, Ruigrok TJ, French P, Jaarsma D, Kistler WM, Meier C, Petrasch-Parwez E, Dermietzel R, Sohl G, Gueldenagel M, Willecke K, Yarom Y. Deformation of network connectivity in the Inferior Olive of Cx36 null-mutant mice is compensated by electrophysiological changes at the single neuron level. Journal of Neuroscience 2003;23:4700-4711 (pubmed)
· Hoogenraad CC, Koekkoek SKE, Akhmanova A, Krugers H, Dortland B, Miedema M, Van Alphen A, Kistler W, Jaegle M, Koutsourakis M, Van Camp N, Verhoye M, Van der Linden A, Kaverina I, Grosveld F, De Zeeuw CI, Galjart N. Williams syndrome-like features and altered protein composition at microtubule tips in CLIP-115 deficient mice. Nat Genet 2002;32(1):116-127 (pubmed)
· Akhmanova A, Hoogenraad CC, Drabek K, Stepanova T, Dortland B, Verkerk T, Vermeulen W, Burgering BM, De Zeeuw CI, Grosveld F, Galjart N. CLASPs are CLIP-115 and CLIP-170 associating proteins, involved in the regional regulation of microtubule dynamics in motile fibroblasts. Cell 2001;104:923-935 (pubmed)
· Sillevis Smitt P, Kinoshita A, De Leeuw B, Moll W, Jaarsma D, Henzen-Logmans S, Vecht CI, De Zeeuw CI, Coesmans MPH, Sekiyama N, Nakanishi S, Shigemoto R. Passive transfer of mGluR1-blocking autoantibodies in Hodgkin’s disease causes cerebellar ataxia. The New England Journal 2000;342(1):21-27 (pubmed)
· De Zeeuw CI, Simpson JI, Hoogenraad CC, Galjart N, Koekkoek SKE, Ruigrok TJH. Microcircuitry and function of the inferior olive. Trends in Neurosci 1998;21:391-400 (pubmed)
· De Zeeuw CI, Hansel C, Bian F, Koekkoek SKE, Van Alphen A, Linden DJ, Oberdick J. Expression of a protein kinase C inhibitor in Purkinje cells blocks cerebellar long term depression and adaptation of the vestibulo-ocular reflex. Neuron 1998;20:495-508 (pubmed)
· De Zeeuw CI, Hoogenraad CC, Goedknegt E, Hertzberg E, Neubauer A, Grosveld F, Galjart N. CLIP-115, a novel brain specific cytoplasmic linker protein, mediates the localisation of dendritic lamellar bodies. Neuron 1997;19(6):1187-1199 (pubmed)