Functional heterogeneity in the macroglial network

Astrocytes and oligodendrocytes, collectively referred to as ‘macroglia’, are ubiquitous cells in the central nervous system that perform essential tissue functions, including buffering potassium, providing metabolic support to neurons, and ensheathing axons to enable rapid saltatory conduction. Yet, despite the important functional roles they fill, very little is known about the physiology of astrocytes and oligodendrocytes in the ventral midbrain, a region that houses dopamine-releasing neurons and is critically involved in reward learning and motivated behaviors. Using a combination of whole transcriptome sequencing, histology, slice electrophysiology and calcium imaging, we profiled the functional and molecular characteristics of ventral midbrain astrocytes. We observed numerous differences between these cells and their telencephalic counterparts, both in their gene expression profile and in their physiological properties. While carrying out this work, we also discovered that a subset of oligodendrocytes express glutamine synthetase (GS), an enzyme that converts glutamate into glutamine. Oligodendrocyte GS appears late in development and is regionally heterogeneous, with higher expression in caudal regions of the central nervous system. Though they don’t appear to express glutamate transporters, oligodendrocytes are extensively coupled to surrounding astrocytes through gap junctions. Selective removal of oligodendrocyte GS led to reduced brain glutamate and glutamine levels, impaired glutamatergic synaptic transmission, and deficits in cocaine-induced locomotor sensitization. Taken together, these data indicate that oligodendrocytes may play a previously unrecognized role in brain glutamate homeostasis. Furthermore, this work provides new insights into the extent of functional astrocyte and oligodendrocyte heterogeneity within the adult brain