Faculty: David R. Hampson, PhD
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, and Department of Pharmacology
Director, CIHR Strategic Training Program in Biological Therapeutics
Chairman, University of Toronto Radiation Protection Authority
General Research Area: Brain development and neurodevelopmental disorders
The developing brain follows a strict chronological progression of events that encompasses cellular proliferation, differentiation, and migration. Brain maturation occurs both prenatally and postnatally and requires precise anatomical and temporal patterns of gene expression and cellular activity. Perturbations in these events can cause neuropathology. Autism spectrum disorders (ASD) are the most common neurodevelopmental disorders. The reported incidence of ASD among newborns has increased dramatically over the past two decades. Mutations in certain genes are known to cause autistic behaviors such as impaired communication and elevated rates of repetitive behaviors and epileptic seizures. Examples of genetic disorders with autistic components include Fragile X Syndrome (FXS) caused by mutations in the FMR1 gene, Dravet Syndrome caused by mutations in the NaV1.1 sodium channel, Rett Syndrome caused by mutations in the MECP2 gene, tuberous sclerosis caused by mutations in the TSC1 and TSC2 genes, and a variety of neurological disorders caused by mutations in the SHANK genes.
A major focus of our research is on FXS where we are seeking to carefully document the complete phenotype, and to develop biological therapeutic agents for treating the disorder. In FXS the protein coded for by the FMR1 gene, Fragile X Mental Retardation Protein (FMRP), is not expressed. Therefore we use the Fmr1 knockout mouse model of FXS. Previously we have studied the effects of potential small molecule therapeutic drugs that act at G-protein coupled receptors; specifically, drugs that act on metabotropic glutamate receptors and GABAB receptors. Using the Fmr1 mouse, our current investigations are directed towards (1) determining the status of myelin (white matter) over the course of brain development and (2) exploring strategies for correcting FXS using viral vector-based biological therapeutic drugs. For the former, we are assessing the status of glia in the CNS, while in the latter we are constructing and testing the efficacy of adeno-associated viral vectors and lenti viral vectors as a means to replace altered or missing proteins (e.g. FMRP). Thus, by necessity research in our laboratory requires knowledge in the areas of molecular biology, protein chemistry, neuroscience and neurology, drug delivery, and behavioral pharmacology.
- David R. Hampson, Shervin Gholizadeh Moghaddam, and Laura K. Pacey (2012)- Pathways to Drug Development for Autism Spectrum Disorders. Clinical Pharmacology and Therapeutics (Nature Publishing Group) 91(2), 189-200. PubMed: 22205199
- Sujeenthar Tharmalingam, Andrew R. Burns, Peter J. Roy, and David R. Hampson (2012) Orthosteric and Allosteric Drug Binding Sites in the C. elegans MGL-2 Metabotropic Glutamate Receptor. Neuropharmacology 63(4), 667-674. PubMed: 22652059
- Laura K. K. Pacey, Ingrid Xuan, Asuka Guan, Dafna Sussman, R. Mark Henkelman, Yan Chen, Christian Thomsen, and David R. Hampson. (2013) Delayed Myelination in a Mouse Model Fragile X Syndrome. Human Molecular Genetics, 22 (19), 3920-3930. PMID: 23740941
- Ingrid C.Y. Xuan and David R. Hampson (2014) Maternal Immune Activation during Pregnancy Induces Gender-Specific Behavioral Effects in Offspring. Plos One, 9 (8) e104433.
- Shervin Gholizadeh, Jason Arsenault, Ingrid Cong Yang Xuan, Laura K. Pacey, and David R. Hampson. (2014) Reduced Phenotypic Severity Following Adeno-Associated Virus Mediated Fmr1 Gene Delivery in Fragile X Knockout Mice. Neuropsychopharmacology (Nature Publishing Group), 39, 3100-11.
- J. Ellegood, E. Anagnostou, B.A. Babineau, J.N. Crawley, L. Lin, M. Genestine, E. DiCicco, D. Bloom, J.K.Y. Lai, J.A. Foster, O. Penagarikano, D.H. Geschwind, L.K. Pacey, D.R Hampson, C.L. Laliberte, G. Horev, A.A. Mills, E. Tam, L.R. Osborne, M. Kouser, F. Espinosa Decerra, Z. Xuan, C.M. Powell, A.Raznahan, D.M. Robins, N. Nakai,J. Nakatani, T. Takumi,M.C.van Eede1, T.M. Kerr,C. Muller, R.D.Blakely, J.Veenstra, D VanderWeele, R.M. Henkelman, and J.P.Lerch. (2015) Clustering Autism: Using Neuroanatomical Differences in 27 Mouse Models to Gain Insight into the Heterogeneity. Molecular Psychiatry (Nature Publishing Group) (2015) 20(1), 118-25. doi: 10.1038/mp.2014.98. PMID: 25199916
- Sujeenthar Tharmalingam, Chiping Wu, and David R. Hampson. (2015) The Calcium-sensing Receptor and Integrins Modulate Cerebellar Granule Cell Precursor Differentiation and Migration. Developmental Neurobiology, 76(4), 375-389. DOI: 10.1002/dneu.22321
- Laura K. K. Pacey, Asuka Guan, Sujeenthar Tharmalingham, Christian Thomsen, and David R. Hampson (2015) - Persistent Astrocyte Activation in the Fragile X Mouse Cerebellum. Brain and Behavior, 2015; 5(10), e00400, doi: 10.1002/brb3.400
- David R. Hampson and Gene J. Blatt. (2015) Autism Spectrum Disorders and Neuropathology of the Cerebellum. Frontiers in Neuroscience, published: 06 November 2015 doi: 10.3389/fnins.2015.00420 http://journal.frontiersin.org/article/10.3389/fnins.2015.00420
- Sujeenthar Tharmalingam and David R. Hampson (2016) The Calcium-sensing Receptor and Integrins in Cellular Differentiation and Migration. Frontiers in Physiology, 7:article 190, pp 1-18. doi: 10.3389/fphys.2016.00190
- Jason Arsenault, Shervin Gholizadeh, Yosuke Niibori, Laura K. Pacey, Sebok K. Halder, Enea Koxhioni, Ayumu Konno, Hirokazu Hirai, and David R. Hampson (2016) - FMRP Expression Levels in Mouse CNS Neurons Determine Behavioral Phenotype. Human Gene Therapy 27(12), 971-981.
- Jakub Sikora, Shaalee Dworsk, E. Ellen Jones, Mustafa A. Kamani, Matthew C. Micsenyi, Tomo Sawada, Pauline Le Faouder, Justine Bertrand-Michel, Aude Dupuy, Christopher K. Dunn, Ingrid Xuan, Josefina Casas, Gemma Fabrias, David R. Hampson, Thierry Levade, Richard R. Drake, Jeffrey A. Medin, and Steven U. Walkley. (2017) Acid ceramidase deficiency in mice results in a broad range of central nervous system abnormalities. American Journal of Pathology, 187 (4), 864-883.