Human Projection Neurons in Health & Disease
The most fundamental and important functions of the human brain are revealed by the deficits that occur during neurological and psychiatric diseases, often with a clear neurodevelopmental origin. Just think about the critical value of consciousness, which is reduced during epileptic seizures; and the importance of initiation and coordination of movements, which is hampered in Parkinson’s Disease and ataxia, respectively, and the relevance of memory formation, which is affected in Alzheimer's Disease, glioma growth and after traumatic brain injury. All these essential functions depend on the activity of the projection neurons and connected cells in our cortices and subcortical nuclei, including those of the cerebral and cerebellar cortex, thalamus, hippocampus, basal gangtia and cerebellar nuclei. For the current project we aim to unravel the electrophysiological and molecular properties as well as the connectivity of the projection neurons in the human brain in health and disease. The electrophysiological and molecular properties of the projection neurons are first studied in tissue obtained from patients with brain tumors with and without epileptic seizures. Gliomas are the most frequent occurring malignant primary brain tumors and many of the patients with glioma develop epileptic seizures when disease progresses. Since gliomas can occur in all the cortical and subcortical regions
mentioned above and invade at the single cell level into the surrounding brain, surgical dissections of these tumors provide tissue containing pathological and normal brain structures of all these regions. This tissue comprises not only cells that
are compromised by the primary (i.e. oncological defects) and secondary (i.e. epileptic defects) pathological effects, but also healthy cells of the surrounding brain.
The electrophysiological and structural cell properties are investigated with patch clamp recordings under voltage, current and dynamic clamp conditions as well as intracellular labeling, while their molecular properties – often relating to cell fate decisions and cell behavior (including guided migration) - are in patient and animal model material investigated at the RNA and protein expression level with the use of state-of-the-art RNA sequencing (currently pushed to the single cell level) and mass spectrometry. Provocative correlations between such electrophysiological, molecular and disease phenotypical data are indeed being further investigated at a mechanistic level in mostly rodent mouse models of the diseases involved. Thus, investigating and analyzing the electrophysiological and molecular properties of healthy and diseased projection neurons (and connected cells) in the human and rodent brain allows us to identify critical cellular properties retevant for e.g. human cognition and sensorimotor behavior.
Another approach to the identification of relevant neuronal subtypes and their function in neurodevelopment is provided by our study aimed at the discovery of the causative genetic mutation in Mendelian nervous system malformations (e.g. GABAergic interneurons in ARX mutation). The identification of several new genes in a multidisciplinary recruited clinical, neuro-radiological and pathological patient cohort (e.e. microcephaly, lissencephaly, polymicrogyria), by high throughput genomic/transcriptomic analysis, is followed by the analysis of the mutation effect in animal and cellular models. Additional value is the direct application of the gained insights in diagnosis and family counseling while understanding of molecular pathogenesis supports exploration of new therapeutic targets.
Collaboration with HBP
HBP aims to uncover and reproduce human brain function using large-scale realistic modelling approaches. Understanding the fundamental structural and cell-physiological properties of projection neurons, in their connected context with other cell types, is critical for this goal' Erasmus MC is one of the largest hospitals in Europe with excellent clinical, health-science and neurobiology teams in various research and clinical departments as well as core technology facilities required to translate knowledge on brain diseases into a fundamental understanding of human brain function and vice versa. Thus the current project fully complements the current basic modelling approaches of HBp and facilitates translation into the clinical field.
Time frame: 2017-2022
Origin: Spontaneous Application
Funding: ERC-adv, NWO, ZonMw, Erasmus MC, Erasmus University Rotterdam, KNAW