Role of perineuronal nets in the CA2 region of the hippocampus in 22q11.2 deletion syndrome

• Applicant: Dr. Margarita Anisimova
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases ; Developmental Neurobiology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2021 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 468470832

The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans, affecting up to 1 in 4000 individuals. It results in various anatomical abnormalities, such as heart defects and immune system disorders, and more importantly leads to developmental delays and psychiatric illnesses including a heightened risk of developing schizophrenia (up to 30% increase in likelihood) and autism spectrum disorder. The offset of neurological changes associated with schizophrenia is closely connected in time to the development of perineuronal nets (PNNs), the specialized extracellular matrix structures responsible for synaptic stabilization, plasticity and neuronal survivability in the adult brain. Several studies have shown that the PNNs development is compromised in schizophrenic patients. Aggrecan is the unique and essential component of the PNNs. It was also shown that the aggrecan gene (ACAN) is downregulated in schizophrenia, making it an interesting candidate that potentially contributes to the PNNs developmental dysfunction in 22q11.2DS. Importantly, only small and specific groups of neurons highly express the aggrecan protein in the brain. One of these groups are the pyramidal neurons in the CA2 area of the hippocampus. Lately, a number of studies has shown that this often-neglected CA2 area of the hippocampus plays a significant role in social cognition. Interestingly, the size and cellular composition of the CA2 region is compromised in many mental disorders which show a decline of cognitive functions, such as schizophrenia, bipolar disorder and Alzheimer’s disease. Considering the significance and commonness of 22q11.2DS in the general population, I want to address the following questions to further understand the neurological changes caused by 22q11.2DS in the hippocampus, specifically in the CA2 area: How are PNNs affected in 22q11.2DS? How is structural synaptic plasticity in CA2 pyramidal neurons altered in 22q11.2DS and how does it correlate with the PNNs structure? Is it possible to prevent the PNNs degradation and disease related changes in the CA2 area of the hippocampus during development? To answer these questions, I am going to focus on a mouse model of the 22q11.2DS, specifically on the new full 3 Mb deletion Del(3.0 Mb)/+ mouse-line. By answering these three questions, I am aiming to gain a better understanding of developmental abnormalities in PNNs in the CA2 area of the hippocampus and how they affect the molecular physiology and structural plasticity of pyramidal CA2 neurons with regard of 22q11.2DS.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professorin Karen Zito, Ph.D.