Team leader : María Cecilia Angulo
Myelinating oligodendrocytes in the CNS are generated from oligodendrocyte precursor cells (OPCs). Our team is interested in understanding the roles of neuronal signaling mechanisms controlling the activity of OPCs and oligodendrocytes during cortical development and in pathological conditions. Our first research line is focused on the study of the close relationship of GABAergic interneurons and OPCs in the developing neocortex. We aim to understand the impact of interneuron activity and GABAergic synapses onto OPCs on oligodendroglia dynamics, cortical maturation and psychiatric diseases. Our second line seeks to define the role of neuronal activity in OPC proliferation and differentiation after a focal demyelination of the adult corpus callosum.
This mouse model of demyelination should allow us to understand the cellular processes that might account for modifications during disease, and to promote a more efficient remyelination by manipulating neuronal activity. Our strategy consists in using a multidisciplinary approach that combines patch-clamp recordings, calcium imaging, immunostaining techniques, optogenetics and advanced optical methods to analyze oligodendroglia physiology during postnatal development and after a demyelination/remyelination process.
Wake H*, Ortiz FC*, Woo DH, Lee P, Angulo MC, Fields D (2015) “Non-synaptic junctions on myelinating glia promote preferential myelination of electrically-active axons”. Nat Commun 6:7844 (*Co-first authors)
Orduz D*, Maldonado PP*, Balia M, Vélez-Fort M, de Sars V, Yanagawa Y, Emiliani V, Angulo MC (2015) Interneurons and oligodendrocyte progenitors form a structured synaptic network in the developing neocortex. eLife 4:e06953 (*Co-first authors)
Sahel, A*, Ortiz, FC*, Kerninon, C, Maldonado PP, Angulo MC#, Nait Oumesmar B# (2015) Alteration of synaptic connectivity of oligodendrocyte precursor cells following demyelination. Front Cell Neurosci 9:77. (*Co-first authors; #Co-last authors)
Balia M*, Vélez-Fort M*, Passlick S, Schäfer C, Audinat E, Steinhäuser C, Seifert G, Angulo MC (2015) Postnatal down-regulation of the GABAA receptor γ2 subunit in neocortical NG2 cells accompanies synaptic-to-extrasynaptic switch in GABAergic transmission mode. Cereb Cortex, 25(4):1114-23 (*Co-first authors)
The principal function of oligodendrocytes in the central nervous system (CNS) is to produce the myelin sheaths that insulate axons and increase the conduction velocity of action potentials. The process of myelination occurs progressively during development in humans and rodents and continues through juvenile stages. Oligodendrocytes derive from oligodendrocyte precursor cells (OPCs) expressing the proteoglycan NG2, also called NG2 cells. By their capacity to generate oligodendrocytes, OPCs play a central role in myelination during postnatal development. Furthermore, this class of progenitors also persists in the mature CNS where they continue to proliferate and generate myelinating oligodendrocytes throughout life. After a demyelinating insult, spontaneous remyelination of axons can occur because OPCs repopulate demyelinating lesions and regenerate oligodendrocytes. OPCs are therefore multifaceted cells that influence brain development and function. Since they are a main pool of progenitors in young and adult stages, they also constitute an important therapeutic target in demyelinating diseases such as Multiple Sclerosis.
1) Interactions between GABAergic interneurons and OPCs in the somatosensory cortex
Although OPCs and interneurons accomplish very different functions (respectively as a glial cell and a neuron), these cells are born from the same embryonic origin, migrate tangentially to the cortex and, once they invade cortical layers, interneurons transiently innervate OPCs through functional synapses. In continuity with our previous studies, we are studying whether these synapses regulate the maturation of OPCs onto mature oligodendrocytes, influencing the construction of neuronal circuits. In addition, we are analyzing the relationship between different subpopulations of OPCs and their ontogenetically related interneurons, and its potential implication in circuit assembly and psychiatric disorders.
2) Interactions between axons and OPCs in white matter
In Multiple Sclerosis (MS) an impaired impulse conduction arises when the immune system attacks myelin sheaths causing the loss of myelin, OL death and a subsequent neurodegeneration associated with functional and cognitive disabilities. However, despite the low regeneration capacity of the CNS, a production of newly formed OLs and a partial myelin repair can occur in this disease. This OL regeneration in response to injury depends mostly on the ability of OPCs to proliferate and differentiate in the damaged site. Several studies have demonstrated that neuronal activity impacts the fate of OPCs and modulates myelination. However, the underlying molecular and cellular mechanisms linking neuronal activity with OPC fate and myelin production are still poorly understood. In addition, while it is known that normal myelination is an activity-dependent process, it is less known whether remyelination is an activity-dependent process in pathological conditions. Our second line seeks to evaluate in vivo the regulation of activity-dependent oligodendrogenesis during myelin repair and to define the signaling and molecular mechanisms implicated in this process.
Our scientific strategy should identify new molecular and cellular mechanisms involved in OPC dynamics, oligodendrogenesis, myelination and myelin repair. It could also open a new route to understand the cellular processes that might account for modifications during behavior and disease and promote more efficient remyelination in demyelinating diseases.
3d Reconstruction of a biocytin-labeled OPC (NG2 Cell)