Role of perineuronal nets in the CA2 region of the hippocampus in 22q11.2 deletion syndrome
Developmental Neurobiology
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
The 22q11.2 deletion syndrome (22q) is the most common de novo microdeletion syndrome in humans, affecting up to 1 in 2000 individuals. Among other physiological deficits, 22q is associated with cognitive impairment and up to 30% of affected individuals will develop various forms of psychosis, including a higher risk of developing schizophrenia in early adolescence. Modern medicine is advanced enough to address and correct almost all physiological deficits associated with 22q, however the treatment of cognitive impairments remains symptomatic without a clear way of addressing the root cause of the specific condition. The goal of the current Walter Benjamin project was to understand how neuronal plasticity mechanisms are altered in 22q and to identify potential targets for development of therapeutics to help alleviate the cognitive impairments associated with the deletion. I used a recently developed full-length deletion (3 Mb) mouse model of 22q that most closely resembles the deletion found in humans. Importantly, during the project I found reduced perineuronal nets density in several areas of hippocampus in 22q mice. Further characterization revealed reduced dendritic spine density, a hallmark that is associated with many neurological disorders linked with intellectual disability and developmental delay. Notably, my preliminary data shows a dramatic decrease in the ability of dendritic spines of 22q mice to exhibit activity-dependent growth and stabilization that is vital for learning and healthy cognitive function. Remarkably, instead I demonstrated that 22q mice exhibit spine shrinkage and destabilization to stimuli that would normally drive growth and stabilization and I found multiple forms of NMDAR-mediated plasticity that are disrupted in 22q mice. Further determining the key players in dendritic spines disfunction is going to open new ways in developing therapeutics to address impaired cognition in individuals with 22q on a molecular level. With an advantage of possible early intervention, we are opening a possibility of changing a developmental trajectory for children with 22q, bringing them potentially closer to the developmental trajectory of neurotypical children.
Publications
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Reduced d-serine levels drive enhanced non-ionotropic NMDA receptor signaling and destabilization of dendritic spines in a mouse model for studying schizophrenia. Neurobiology of Disease, 170, 105772.
Park, Deborah K.; Petshow, Samuel; Anisimova, Margarita; Barragan, Eden V.; Gray, John A.; Stein, Ivar S. & Zito, Karen
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Activity-Dependent Stabilization of Nascent Dendritic Spines Requires Nonenzymatic CaMKIIα Function. The Journal of Neuroscience, 44(2), e1393222023.
Claiborne, Nicole; Anisimova, Margarita & Zito, Karen
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APP Fragment Controls Both Ionotropic and Non-Ionotropic Signaling of NMDA Receptors.
Dunot, Jade; Moreno, Sebastien; Gandin, Carine; Pousinha, Paula; Amici, Mascia; Dupuis, Julien; Anisimova, Margarita; Winschel, Alex; Mensch, Maria; Bethus, Ingrid; Giudici, Camilla; Hampel, Heike; Wefers, Benedikt; Wurst, Wolfgang; Ashby, Michael; Laube, Bodo; Zito, Karen; Mellor, Jack; Groc, Laurent ... & Marie, Helene
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Disruption of neuronal plasticity mechanisms in 22q11.2 deletion syndrome model mice. 4th biennial 22q11 deletion syndrome symposium. Stanford University, USA
Anisimova M., Petshow S.J. & Zito K.
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Molecular signaling pathways that drive changes in brain structure in health and schizophrenia. 8th annual UC Davis Postdoctoral Research Symposium. UC Davis, USA
Anisimova M., Petshow S.J. & Zito K.
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Neuronal FOS reports synchronized activity of presynaptic neurons.
Anisimova, Margarita; Lamothe-Molina, Paul J.; Franzelin, Andreas; Aberra, Aman S.; Hoppa, Michael B.; Gee, Christine E. & Oertner, Thomas G.
