Brain Plasticity in Health and Disease

My research focusses on molecular, cellular and network mechanisms of neuronal and synaptic plasticity in normal brain function and in situations of impaired or altered plasticity, such as healthy aging, Alzheimer’s disease, schizophrenia and neuronal injury.

Cognitive decline in aging and Alzheimer’s disease
Alzheimer’s disease is the second most prevalent neurodegenerative disorders and characterized by the progressive loss of specific populations of neurons. The reasons for this selective vulnerability are not clear. Using (pharmaco)genetic mouse models we try to identify molecular markers of early, presymptomatic Alzheimer’s disease and design treatment strategies thereof. We currently focus on interneurons in the hippocampus that appear to be affected in both healthy aging and Alzheimer’s disease.

Hippocampal Extracellular Matrix Levels and Stochasticity in Synaptic Protein Expression Increase with Age and Are Associated with Age-Dependent Cognitive Decline.
MJ Vegh, A Rausell, M Loos, CM Heldring, W Jurkowski, P van Nierop, I Paliukhovich, KW Li, A del Sol, AB Smit, S Spijker, and RE van Kesteren
Mol Cell Proteomics 13:2975-2985 (2014)

Reducing Hippocampal Extracellular Matrix Reverses Early Memory Deficits in a Mouse Model of Alzheimer’s Disease.
MJ Vegh, CM Heldring, W Kamphuis, S Hijazi, AJ Timmerman, KW Li, P van Nierop, HD Mansvelder, EM Hol, AB Smit, and RE van Kesteren
Acta Neuropathol Comm 2:76 (2014)

Functional analysis of schizophrenia risk genes
Schizophrenia is a mental disorder with a complex genetic origin and many potential schizophrenia risk genes have been identified. We are testing the hypothesis that risk genes/mutations act together on the development of neuronal networks in the brain. We use a cell culture approach combined with high-throughput and high-content microscopy. Both primary mouse embryonic neurons and human iPSC-derived neurons are used to study the effects of risk genes and risk mutations on the development of neuronal networks in vitro. We contribute to several international schizophrenia research consortia (SUN, COSYN, InSens)

High-Content Screening at CNCR.

High Content Screening in Neurodegenerative Diseases.
S Jain, RE van Kesteren, and P Heutink
J Vis Exp e3452 (2012)

Molecular mechanisms underlying synapse formation and synaptic plasticity
Neurons need to dynamically change the strength and number of their synaptic connections in order to respond to and retain memory for particular stimuli. These changes require synapse autonomous molecular mechanisms, but also changes in nuclear gene expression. We use transgenic mouse models to study both synapse autonomous and transcription-dependent mechanisms underlying synapse formation, synapse function and synaptic plasticity.

Ubiquitin Ligase Trim3 Controls Hippocampal Plasticity and Learning by Regulating Synaptic Gamma-Actin Levels.
J Schreiber, MJ Vegh, J Dawitz, T Kroon, M Loos, D Labonté, KW Li, P van Nierop, MT Van Diepen, CI De Zeeuw, M Kneussel, RM Meredith, AB Smit, and RE van Kesteren
J Cell Biol 211:569-586 (2015)

Local Synthesis of Actin-Binding Protein Beta-Thymosin Regulates Neurite Outgrowth.
RE van Kesteren, C Carter, HMG Dissel, J van Minnen, Y Gouwenberg, NI Syed, GE Spencer, and AB Smit
J Neurosci 26:152-157 (2006)

Transcription factors that control regenerative neurite growth
In contrast to the peripheral nervous system, neurons in the central nervous system fail to regenerate injured axons. Using the sensory neurons in the rat dorsal root ganglion as a model system we identified several transcription factors that control neuronal regeneration. We use these data to reconstruct transcription regulatory networks underlying successful neuronal regeneration using experimental and computational approaches, and to identify key transcription factors that may be used to promote regeneration of injured central neurons.

Llm3d: A Log-Linear Modeling-Based Method to Predict Functional Gene Regulatory Interactions from Genome-Wide Expression Data.
G Geeven, HD Macgillavry, R Eggers, MM Sassen, J Verhaagen, AB Smit, MCM De Gunst, and RE van Kesteren
Nucleic Acids Res 39:5313-5327 (2011)

Nfil3 and Camp Response Element-Binding Protein Form a Transcriptional Feedforward Loop That Controls Neuronal Regeneration-Associated Gene Expression.
HD Macgillavry, FJ Stam, MM Sassen, L Kegel, WTJ Hendriks, J Verhaagen, AB Smit, and RE van Kesteren
J Neurosci 29:15542-15550 (2009)