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Department of Molecular and Cellular Neurobiology

The MCN department aims at taking a Systems Biology approach to study brain function. This means we try to span and connect several levels of investigation, i.e. from molecules up to behavior.

In particular, we investigate the molecular and cellular mechanisms that underlie the formation and plasticity of synapses in animal models of brain disease. For this, we focus on mechanisms of synapse formation during development, adult plasticity as well as de- and regeneration of central neurons.

At the synapse we strive to solve the architecture of protein assemblies that determine synaptic function and allow for plasticity. For this we use forefront proteomics technologies to establish novel modulatory interactions in protein networks. For functional dissection of synaptic proteins we use high-content automated microscopy involving gene over-expression and knockdown approaches in cultured neurons. Neuron-glial interactions are studied to understand the hitherto underestimated role of glial cells in plasticity of the brain. Ligand-gated ion channels are studied to understand their structure-function relationships and their contribution to synaptic function. We use various rodent experimental paradigms, to study specific brain diseases predominantly in the field of cognitive, impulsive, addictive and depressive disorders. This behavioural research is making use of novel methods in high-throughput phenotyping. In order to understand our animal models of brain disease we integrate our molecular, cellular and behavioural approaches thereby reaching a systems level description. Informatics is key to success for this integration.

MCN is partner in the Dutch NeuroBsik Mouse Phenomics consortium, is partner in the Center for Medical Systems Biology (CMSB), leads and is partnering in three Top Institute Pharma projects. MCN is coordinator of the European consortium SynSys, Neurocypres, and partner in the EU training networks Braintrain and Cerebnet.

MCN harbors approximately 40 scientists in 6 research teams.

Recent highlights from the MCN lab:

Von Engelhardt J, Mack V, Sprengel R, Kavenstock N, Li KW, Stern-Bach Y, Smit AB, Seeburg PH, and Monyer H. CKAMP44: A brain specific protein that attenuates short-term synaptic pasticity in Dentate Gyrus. Science 2010 327,1518-1522.

Spijker S, Van Zanten JS, De Jong S, Penninx BW, van Dyck R, Zitman FG, Smit JH, Ylstra B, Smit AB, Hoogendijk WJ. Stimulated gene expression profiles as a blood marker of major depressive disorder. Biol Psychiatry. 2010 68(2):179-86.

Verheijen MH, Camargo N, Verdier V, Nadra K, de Preux Charles AS, Macdard JJ, Luoma A, Crowther M, Inouye H, Shimano H, Chen S, Brouwers JF, Helms JB, Feltri ML, Wrabetz L, Kirschner D, Chrast R, Smit AB. SCAP is required for timely and proper myelin membrane synthesis. Proc Natl Acad Sci U S A. 2009 106(50):21383-8.

Van den Oever MC, Goriounova NA,+ Li KW+, Van der Schors RC, Binnekade R, Schoffelmeer AN, Mansvelder HD, Smit AB, Spijker S, De Vries TJ. Prefrontal cortex AMPA receptor plasticity is crucial for cue-induced relapse to heroin-seeking. Nat Neurosci. 2008 11(9):1053-8.

Ulens C, Hogg RC, Celie PH, Bertrand D, Tsetlin V, Smit AB, Sixma TK.
Structural determinants of selective alpha-conotoxin binding to a nicotinic
acetylcholine receptor homolog AChBP. Proc Natl Acad Sci U S A. 2006 103(10):3615-20.

Celie PH, Kasheverov IE, Mordvintsev DY, Hogg RC, van Nierop P, van Elk R, van
Rossum-Fikkert SE, Zhmak MN, Bertrand D, Tsetlin V, Sixma TK, Smit AB. Crystal
structure of nicotinic acetylcholine receptor homolog AChBP in complex with an
alpha-conotoxin PnIA variant. Nat Struct Mol Biol. 2005 12(7):582-8.

Celie, P, van Rossum-Fikkert S, van Dijk WJ, Brejc K, Smit AB. and Sixma TK (2004) Nicotine and carbamoylcholine binding to nicotinic acetylcholine receptors as studied by AChBP crystal structures. Neuron 41(6):907-14.

Smit AB, Syed NI, Schaap D, Van Minnen J, Klumperman J, Kits KS, Lodder H, Van der Schors RC, Van Elk R, Sorgedrager B, Brejc K, Sixma TK and Geraerts WPM. (2001) A glia-derived modulator of cholinergic synaptic transmission. Nature 411, 261-268.

Brejc K, Van Dijk WJ, Klaassen RV, Schuurmans M, Van der Oost J, Smit AB and Sixma TK (2001) Crystal structure of AChBP reveals the ligand-binding domain of nicotinic receptors. Nature 411, 269-276.

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