Synaptic Physiology

Molecular mechanisms underlying the formation and plasticity of inhibitory synapses

Neuronal circuits in our brain have an enormous capacity to adapt during development, when learning, or in response to injury or disease. In a healthy brain, changes in excitatory and inhibitory synapses are coordinated to preserve neuronal and network function. Recent experimental and computational studies have demonstrated that particularly inhibitory synapses, even though they are only ~15% of all synapses in the brain, are very important in controlling synaptic plasticity and shaping information processing in the brain. Inhibitory synapses also represent a vulnerability of the brain. Impaired inhibitory signaling is at the basis of many neurodevelopmental and other brain disorders, including autism and early stages of Alzheimer’s disease.

In the Wierengalab we are interested in the role of inhibitory synapses at the molecular, cellular and network level. We study the molecular mechanisms underlying the formation an plasticity of inhibitory synapses using a combination of two-photon microscopy, electrophysiology and molecular approaches in brain slices. Our live imaging studies show that inhibitory synapses are incredibly dynamic. They can be formed or eliminated rapidly depending on local demand. We already unraveled some of the molecular signals that govern the formation of inhibitory synapses and identified an unexpected role for endocannabinoids in local coordination of excitatory and inhibitory synapses within dendrites. Ongoing studies examine changes in inhibitory synapses when normal development is disturbed and in early stages of Alzheimer’s disease.

Research group information

Click on one of the links below for more information about this research group or contact one of the members of this group.

People

Principal Investigator

Prof. dr. Corette Wierenga

Postdoc

PhD candidates

Research assistant

Camila Medina Polanco

Key grants and prizes

Prices and Awards

2012 NWO VIDI
2012 NWO Aspasia
2008 UNESCO-L'Oréal award ‘For Women in Science’ Germany National award (in Germany) for excellent and promising young female scientists in natural sciences
1999 Young Physiologist Price of the Dutch Physiology Society Price for the best oral presentation at the Young Phsyiologists Day
1991 Bronze medal at the 2nd International Biology Olympiad in Machatskala (Russia) The International Biology Olympiad is a competition for high school students. Each country sends four students, who won the national competitions.

Research grants

2022-2026 Alzheimer Nederland grant (300.000 EUR) ‘Investigating effects of Aβ oligomers on presynaptic nanostructure and function’
2020-2024 NWO-ENW klein-I grant (350.000 EUR) ‘How do dendrites coordinate adjacent excitatory and inhibitory inputs?’
2019-2021 Alzheimer Nederland grant (100.000 EUR) ‘Linking amyloid β-induced microglia activation and network hyperexcitability’
2017-2022 ZonMW TOP grant (225.000 of 675.000 EUR – project leader) ‘Early developmental processes underlying sensory deficits in neurodevelopmental disorders’
2017-2022 FOM program (346.000 of 1.755.000 EUR – co-applicant) ‘NeuroPhotonics: unraveling the physics of signaling in intact neuronal networks’
2017-2019 Alzheimer Nederland grant (100.000 EUR) ‘Amyloid β-induced pathology of inhibitory synapses’
2016-2021 ALW grant (284.474 EUR - with Louk Vanderschuren) ‘How early social experience shapes higher brain function’
2015-2019 FOM grant (400.000 EUR) ‘Two-photon microcopy of nonlinearities in dendritic computation’
2014-2015 Dynamics of Youth Seeding grant (100.000 EUR - with Louk Vanderschuren) ‘How early social experience shapes brain development’
2012-2017 VIDI grant from the Dutch Scientific Organization (NWO) (800.000 EUR) ‘Balancing the Brain: Local Interactions between Excitatory and Inhibitory Synapses’
2010-2013 Marie Curie European Reintegration Grant (ERG) (45.000 EUR) CV Corette Wierenga Page 5 ‘Local interactions between GABAergic and glutamatergic plasticity’
2008-2010 Christiane Nüsslein-Volhard Fellowship (9.600 EUR)
2007-2009 Marie Curie Intra-European Fellowship (IEF) (72.700 EUR) ‘The role of filopodia in synapse formation in absence of dendritic spines’
2006-2007 Alexander von Humboldt Research Fellowship (27.000 EUR) ‘The role of filopodia in synaptogenesis in the absence of dendritic spines’
2003-2004 Postdoctoral Fellowship of the Sloan-Swartz Center for Theoretical Neurobiology (30.000 USD)
2002-2003 NWO TALENT fellowship (34.000 USD) ‘Short-term plasticity of excitatory synapses after homeostatic plasticity’

Key publications

Peer-reviewed articles

Bijlsma A, Omrani A, Spoelder M, Verharen JPH, Bauer L, Cornelis C, de Zwart B, van Dorland R, Vanderschuren LJMJ, Wierenga CJ (2022) Social play is critical for the development of prefrontal inhibitory synapses and cognitive flexibility in rats. BioRxiv.
Liang J, Kruijssen DLH, Verschuuren ACJ, Voesenek BJB, Benavides F, Sáez Gonzalez M, Ruiter M, Wierenga CJ (2021) Axonal CB1 receptors mediate inhibitory bouton formation via cAMP increase. Journal of Neuroscience, 41: 8279-8296. CV Corette Wierenga Page 2
Homberg J et al. (2021) The continued need for animals to advance brain research. Neuron 109: 2374-2379.
Ruiter M, Lützkendorf C, Liang J, Wierenga CJ (2021) Amyloid-β oligomers induce only mild changes to inhibitory bouton dynamics. Journal of Alzheimer’s Disease Reports, 5: 153-160.
Lindhout FW, Portegies S, Kooistra R, Herstel LJ, Stucchi R, Hummel JJA, Scheefhals N, Katrukha EA, Altelaar M, MacGillavry HD, Wierenga CJ, Hoogenraad CC (2021) Centrosome-mediated microtubule remodeling during axon formation in human iPSC-derived neurons. EMBO Journal e106798.
Peerboom C, Wierenga CJ (2021) The postnatal GABA shift: A developmental perspective. Neuroscience and Biobehavioral Reviews 124: 179–192.
Herstel LJ, Wierenga CJ (2021) Network control through coordinated inhibition. Current Opinion in Neurobiology 67: 34-41.
Ruiter M, Herstel LJ, Wierenga CJ (2020) Reduction of dendritic inhibition in CA1 pyramidal neurons in amyloidosis models of early Alzheimer’s disease. Journal of Alzheimer’s Disease 78: 951-964.
Lindhout FW, Kooistra R, Portegies S, Herstel LJ, Stucchi R, Snoek BL, Altelaar M, MacGillavry MD, Wierenga CJ, Hoogenraad CC (2020) Quantitative mapping of transcriptome and proteome dynamics during polarization of human iPSC-derived neurons. eLIFE 9: e58124.
Genzel L. et al. (2020) How the COVID-19 pandemic highlights the necessity of animal research. Current Biology 30: 1009-1035.
Kruijssen DLH, Wierenga CJ (2019) Single Synapse LTP: a Matter of Context? Frontiers in Cellular Neuroscience 13: 496.
Hu HY, Kruijssen DLH, Frias CP, Rózsa B, Hoogenraad CC, Wierenga CJ (2019) Endocannabinoid signaling mediates local dendritic coordination between excitatory and inhibitory synapses. Cell Reports 27: 666-675.
Frias CP, Liang J, Bresser T, Scheefhals L, van Kesteren M, van Dorland R, Hu HY, Bodzeta A, van Bergen en Henegouwen PMP, Hoogenraad CC, Wierenga CJ (2019) Semaphorin4D induces inhibitory synapse formation by rapid stabilization of presynaptic boutons via MET coactivation. Journal of Neuroscience 39: 4221-4237.
Nijhof SL Vinkers CH, van Geelen SM, Duijff SN, Achterberg EJM, van der Net J, Veltkamp RC, Grootenhuis MA, van de Putte EM, Hillegers MHJ, van der Brug AW, Wierenga CJ, Benders MJNL, Engels RCME, Van der Ent CK, Vanderschuren LJMJ, Lesscher HMB (2018) Healthy play, better coping: The importance of play for the development of children in health and disease. Neuroscience & Biobehavioral Reviews 95: 421-429.
Niculescu D, Michaelsen-Preusse K, Güner Ü, van Dorland R, Wierenga CJ, Lohmann C (2018) A BDNF-mediated push-pull plasticity mechanism for synaptic clustering. Cell Reports 24: 2063- 2074.
Schätzle P, Esteves da Silva M, Tas RP, Katrukha EA, Hu HY, Wierenga CJ, Kapitein LC, Hoogenraad CC (2018) Activity-dependent actin remodeling at the base of dendritic spines promotes microtubule entry. Current Biology 28: 2081-2093.
Schulte JT, Wierenga CJ*, Bruining H* (2018) Chloride transporters and GABA polarity in developmental, neurological and psychiatric conditions. Neuroscience & Biobehavioral Reviews 90: 260-271. * co-senior author
Wierenga CJ (2017) Live imaging of inhibitory axons: Synapse formation as a dynamic trial-anderror process. Brain Research Bulletin 129: 43-49. CV Corette Wierenga Page 3
Harschnitz O, van den Berg LH, Johansen LE, Jansen MD, Kling S, Vieira De Sá R, Vlam L, van Rheenen W, Karst H, Wierenga CJ, Pasterkamp RJ, van der Pol WL (2016) Autoantibody pathogenicity in a multifocal motor neuropathy iPSC-derived model. Annals of Neurology 80: 71-88.
20. Kellner Y, Fricke S, Kramer S, Iobbi C, Wierenga CJ, Schwab ME, Korte M, Zagrebelsky M (2016) Nogo-A controls structural plasticity at dendritic spines by rapidly modulating actin dynamics. Hippocampus 26: 816-831.
Lenz M, Galanis C, Müller-Dahlhaus F, Opitz A, Wierenga CJ, Szabó G, Ziemann U, Deller T, Klaus Funke, and Vlachos A (2016) Repetitive magnetic stimulation induces plasticity of inhibitory synapses. Nature Communications 7: 10020.
Esteves da Silva M, Adrian M, Schätzle P, Lipka J, Watanabe T, Cho S, Futai K, Wierenga CJ, Kapitein LC, Hoogenraad CC (2015) Positioning of AMPA receptor-containing endosomes regulates synapse architecture. Cell Reports 13: 933-943.
Müllner F, Wierenga CJ*, Bonhoeffer T* (2015) Precision of inhibition: Dendritic inhibition by individual GABAergic synapses on hippocampal pyramidal cells is confined in space and time. Neuron 87, 576-589. * co-senior author
Adrian M, Kusters R, Wierenga CJ, Storm C, Hoogenraad CC and Kapitein LC (2014) Barriers in the Brain: Resolving Dendritic Spine Morphology and Compartmentalization. Frontiers in Neuroanatomy 8: 142.
Gomis-Rüth S, Stiess M, Wierenga CJ, Meyn L, Bradke F (2014) Single cell axotomy of cultured hippocampal neurons integrated in neuronal circuits. Nature Protocols 9: 1028-1037.
Frias CP, Wierenga CJ (2013) Activity-dependent adaptations in inhibitory axons. Frontiers in Cellular Neuroscience 7: 219.
Schuemann A, Klawiter A, Bonhoeffer T, Wierenga CJ (2013) Structural plasticity of GABAergic axons is regulated by network activity and GABAA receptor activation. Frontiers in Neural Circuits 7: 113.
Vogels TP, Froemke RC, Doyon N, Gilson M, Haas JS, Liu R, Maffei A, Miller P, Wierenga CJ, Woodin MA, Zenke F and Sprekeler H (2013) Inhibitory synaptic plasticity: spike timingdependence and putative network function. Frontiers in Neural Circuits 7: 119.
Keck T, Scheuss V, Jacobsen I, Wierenga CJ, Eysel U, Bonhoeffer T, Hübener M (2011) Loss of sensory input causes rapid structural changes of inhibitory neurons in adult mouse visual cortex. Neuron 71: 869-882.
Wierenga CJ, Müllner FE, Rinke I, Keck T, Stein V, Bonhoeffer T (2010) Molecular and electrophysiological characterization of GFP-expressing interneurons in GAD65-GFP mice. PLoS One 5: e15915.
Wierenga CJ, Becker N, Bonhoeffer T (2008) GABAergic synapses are formed without the involvement of dendritic protrusions. Nature Neuroscience, 11: 1044-1052.
Becker N, Wierenga CJ, Fonseca R, Bonhoeffer T, Nägerl UV (2008) Presynaptic boutons show a large degree of turnover after hippocampal LTD resulting in the removal of synaptic connections. Neuron 60:590-597.
Gomis-Rüth S, Wierenga CJ, Bradke F (2008) Plasticity of polarization: changing axonal and dendritic identity in mature neurons. Current Biology 18: 992-1000.
Wierenga CJ, Walsh MF, Turrigiano GG (2006) Temporal regulation of the expression locus of homeostatic plasticity. Journal of Neurophysiology 96: 2127-2133.
Wierenga CJ, Ibata K, Turrigiano GG (2005) Postsynaptic expression of homeostatic plasticity at neocortical synapses. Journal of Neuroscience 25: 2895-2905. CV Corette Wierenga Page 4
Wierenga CJ, Wadman WJ (2003) Functional relation between interneuron input and population activity in the hippocampal CA1 area. Neuroscience 118: 1129-1139.
Wierenga CJ, Wadman WJ (2003) Excitatory inputs to CA1 interneurons show selective synaptic dynamics. Journal of Neurophysiology 90:811-821.
Wierenga CJ, Wadman WJ (1999) Miniature inhibitory postsynaptic currents in CA1 pyramidal neurons after kindling epileptogenesis. Journal of Neurophysiology 82:1352-1362.

Book Chapter

Hoogenraad CC, Wierenga C (2014) Neurons, Overview. In: Aminoff M.J. and Daroff R.B. (eds.) Encyclopedia of the Neurological Sciences, 2nd edition, vol. 3, pp. 456-458. Oxford: Academic Press.

Contact information

024-3653276

Postal address

Postbus 9010
6500GL NIJMEGEN

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