The role of synaptic communication between neurons and NG2-glia in the adult brain

• Applicant: Katrin Volbracht, Ph.D.
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2020 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 444583389

The central nervous system (CNS) consists of neurons and glial cells. NG2-glia are the main proliferating cells in the adult brain where they comprise around 5% of all cells. They are also known as oligodendrocyte progenitor cells (OPCs) and are, as their name implies, able to generate new oligodendrocytes throughout life. Oligodendrocytes form the CNS myelin that is essential for fast and energy efficient nerve conduction and for the correct timing and synchronisation of signals. Activity dependent myelination allows for CNS plasticity as the generation of new oligodendrocytes has been shown to be required for motor learning. Although most of the myelin is formed early in life, there is growing evidence that myelination continues into late adulthood and that some NG2-glia need to continuously differentiate into new oligodendrocytes in the adult brain to maintain the myelin structure and motor abilities. However, it is not yet fully understood how NG2-glia differentiation in the adult CNS is regulated. Moreover, the high number and even distribution of NG2-glia throughout the CNS, also in areas that never become myelinated, suggest that NG2-glia serve some other purpose in addition to their role as progenitors, but what that function could be is still unclear.Interestingly, NG2-glia also form synapses with neuronal axons and act as post-synapse for neuronal inputs. These synapses, which only occur on unmyelinated axonal segments, may be regulators of NG2-glia differentiation. However, the data regarding the function of neuron-NG2-glia synapses are rather contradictory, and depending on the experimental design, researchers found that NG2-glia synapses may affect proliferation, differentiation, cell survival or migration. My aim in the proposed project is thus to study the function of NG2-glia synapses in the adult CNS using a novel and more targeted approach. To specifically disrupt the neuron-glia synaptic communication we have generated a new mouse model with an inducible oligodendrocyte lineage specific conditional deletion in the gene for Shank3, a central scaffold protein at the postsynaptic density. The deletion of SHANK3 in humans disrupts excitatory neuronal synapses and causes the Phelan-McDermid syndrome, an autism spectrum disorder (ASD). Induction of the transgene in our mice leads to the deletion of the major isoforms of Shank3 specifically in oligodendrocyte lineage cells to disrupt NG2-glia synapses but leave neuronal synapses intact. I will study the effect of this cell specific Shank3 deletion on NG2-glia proliferation, differentiation and on myelin as well as on the morphology and function of the neuron-NG2-glia synapses themselves. Moreover, I will assess how these cellular changes affect the motor, cognitive and social abilities of the mice. The results of this project will not only help to answer the important physiological question of the function of NG2-glia in the adult CNS but may also uncover a role for NG2-glia in ASD.

• DFG Programme: WBP Position