Brigitte van Zundert graduated as a Biochemist from the Dutch University HLO, Faculty of Science and Technology, in 1993. She has been specializing in the field of Molecular and Cellular Biology and received her Master degree from the University of Utrecht (The Netherlands) in 1996 and her Ph.D. from the University of Concepción (Chile) in 2002, in which she started to study neuronal transmission and plasticity. She continued to work on these topics during her 3 year duration postdoctoral training at the Massachusetts University of Technology (MIT, USA) and Harvard/Massachusetts General Hospital (MGH, USA). In 2005, Dr. van Zundert started as an Assistant Professor her independent laboratory (Laboratory of Neuroplasticity) at the University of Concepción, at which she became an Associate Professor in 2010. In 2011 she moved to the Andres Bello University (Santiago, Chile), to be incorporated as an associate researcher at the Center for Biomedical Research.
The long-term goal of my laboratory (Laboratory of Neuroplasticity) is to understand the basic cellular and molecular mechanisms that control neuronal plasticity, learning and memory. With the help of numerous young investigators, including a postdoctoral fellow, PhD students, and undergraduate students in Biochemistry and Biotechnology, we have started three related lines of investigations (see below): for each of these, we use a multidisciplinary approach including electrophysiology, molecular and cellular biology, fluorescence techniques, and behavioural studies.
Reactivation of plasticity in the adult brain
It is well known that structural plasticity (e.g. spine and dendrite growth) and functional plasticity (e.g. LTP) becomes very limited as the central nervous system matures. This phenomenon has serious consequences and limits our ability to learn new capacities (e.g. a new language or playing an instrument) or to adapt when the brain is damaged due to injury or as a consequence of neurodegenerative disorders such as Amyotrophic Lateral Sclerosis (ALS), Alzheimer´s disease, or Parkinson´s disease. Many studies over several decades have revealed that the excitatory glutamate NMDA receptors on post-synaptic cells play a key role in regulating plasticity. However, the precise molecular mechanisms whereby activated NMDA receptors send signals to the nucleus, to regulate expression of certain genes that then promote or limit plasticity, have not yet been elucidated. A likely reason for this is that, in addition to the different types of NMDA receptors, more than 400 other proteins are located at the excitatory synapse. We argue that not all of these proteins interact with each other, but that the synapse has specific micro-domains, within which precise interactions between different types of NMDA receptors, scaffolding and signalling proteins define whether this postsynaptic neuron upon activation will either increase or decrease plasticity (van Zundert et al., TiNS 2004). A central hypothesis underlying our work is that during early development, the scaffold protein SAP102 couples the synaptic NR2B-containing NMDA receptors to the signalling proteins RasGRF1 and CaMKII, which in turn allows structural and functional plasticity; with maturation, the expression of the scaffold protein PSD-95 and NR2A-containg NMDA receptors increases, and these proteins replace the NR2B/SAP102 synaptic complexes, thereby limiting plasticity. This hypothesis has the important implication that reinsertion NR2B-NMDA receptors at the synapse, or coupling RasGRF1 and/or CaMKII to synaptic NR2A-NMDA receptors, can re-activate plasticity in the mature central nervous system. Using a variety of molecular tools, we have been able to alter the context of synaptic micro-domains and regulate dendrite outgrowth and spine morphology (indicators of structural plasticity) in developing and mature cultured neurons (Sepulveda et al., J. Neurophysiology 2010; Bustos et al., Plos One 2014). Currently, we have been focusing our research to seek to determine precise epigenetic mechanisms that control expression of PSD95 and establish its subsequent impact on neuronal phenotype and function (Henriquez et al., Molecular and Neuroscience 2013; Bustos et al., manuscript in preparation).
Primary mechanisms underlying ALS
Amyotrophic lateral sclerosis (ALS) is a devastating, incurable disease caused by the degeneration of cranial and spinal motoneurons in adulthood. The British physicist Stephan Hawkins is one of the most famous patients suffering from this terrible disorder. It is well known that gain of an unknown toxic function(s) resulting from mutations in the enzyme superoxide dismutase (SOD1) are responsible for a proportion of familial ALS; >150 different mutations have already been identified. However, despite the availability of good transgenic mice models for many years, surprisingly, we do not yet know how these mutations in SOD1 are associated with disease pathogenesis, and when the pathological onset of the disease actually starts. We showed that, months before motoneuron degeneration and clinical symptoms appear, motoneurons and interneurons in acute slice preparations from neonatal hSOD1G93A mice (P4-10) display morphological and functional changes: these include increases in voltage-sensitive sodium (Nav) mediated excitability, and synaptic neurotransmission (van Zundert et al., Journal Neuroscience 2008). Such changes are the earliest yet reported for the hSOD1G93A mouse, or for any other rodent models of adult-onset neurodegenerative diseases. Since the last couple of years, we have established a culture model to study the molecular mechanisms that initiate this adult-onset disease. Importantly, we have found that that astrocytes derived from transgenic mice expressing different mutant form of the human SOD1 and TDP43 proteins, release a toxic component to the media that acutely enhances the neuron´s excitability mediated by Nav channels (Fritz et al., Journal of Neuroscience 2013; Rojas et al., Frontiers in Cellular Neuroscience 2014, 2015). Recently, we have started to work with patient-specific induced pluripotent stem cells (iPSCs) derived from human ALS patients to differentiated them into astrocytes. We believe that the results of our study will have far-reaching implications for ALS, from the pathogenic and therapeutic standpoint (reviewed in van Zundert Journal of Cellular Biochemistry 2012).
- Bustos, F.J., Varela-Nallar, L., Campus, M., Henriquez, B., Philips, M., Opazo, C., Aguayo, L.G., Montecino, M., Constantine-Paton, M., Inestrosa, N., van Zundert, B. (2014) PSD-95 suppresses dendritic arbor development in mature hippocampal neurons by occluding the clustering of NR2B-NMDA receptors. Plos One 9(4): e94037.
- Henriquez, B., Bustos, F.J., Aguilar, R.A., Becerra, A., Simon, F., Montecino, M., van Zundert, B. (2013) Polycomb group proteins Ezh1 and Ezh2 differentially regulate PSD-95 gene expression in developing hippocampal neurons. Mol. Cell. Neurosci, 57: 130-43.
- Rojas, F., Cortes, N., Abarzua, S., Dyrda, S., van Zundert, B. (2014)Astrocytes expressing mutant SOD1 and TDP43 trigger motoneuron death that is mediated via sodium channels and nitroxidative stress. Front. Cell. Neurosci. 8:24.
- Fritz, E., Izaurieta, P., Weiss, A., Mir, F.R., Rojas, P., Gonzalez, D., Rojas, F., Brown, R.H. Jr, Madrid, R., van Zundert, B. (2013) Mutant SOD1-expressing astrocytes release toxic factors that trigger motor neuron death by inducing hyper-excitability. J. Neurophysiol, 109 (11): 2803-2814.
- van Zundert, B., Izaurieta, P., Fritz, E., Alvarez, F.J. (2012) Early pathogenesis in the adult-onset neurodegenerative disease amyotrophic lateral sclerosis. J. Cell. Biochem.113:3301-3312.