Glial cells are important components of brain function. However, their contributions to synaptic transmission or to CNS development and injury processes still require mechanistic explanations. In my presentation I will discuss several genetic mouse models that helped us to obtain a better understanding of the CNS.
In the cerebellum, Bergmann glial (BG) cells express α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) composed exclusively of GluA1 and/or GluA4 subunits. With the use of conditional gene inactivation, we found that the majority of cerebellar GluA1/A4-type AMPARs are expressed in BG cells. In young mice, deletion of BG AMPARs resulted in retraction of glial appendages from Purkinje cell (PC) synapses, increased amplitude and duration of evoked PC currents, and a delayed formation of glutamatergic synapses. In adult mice, AMPAR inactivation also caused retraction of glial processes. The physiological and structural changes were accompanied by behavioral impairments in fine motor coordination. Thus, BG AMPARs are essential to optimize synaptic integration and cerebellar output function throughout life.
Similarly, we used conditional gene targeting to ablate the essential subunit of NMDA receptors (NR1) in mature oligodendrocytes in vivo. Focussing on the optic nerve, we discovered that activation of oligodendroglial NMDA receptors in development marks a previously unrecognized neuronal (axonal) stimulation of myelin formation. Moreover, by using a well-established ex vivo model of ischemia and comparing NMDA receptor mutants and wildtype optic nerves we identifed that glutamate-mediated signals can be "axon-protective" under hypoxic/hypoglycemic conditions, rather than simply toxic as previously hypothesized. We therefore can propose a new model in which oligodendroglial NMDA receptor activation orchestrates a metabolic support for the axon that is elegantly coupled to axonal energy needs.
Glial fate-mapping experiments employed the transgenic split-Cre/loxP system as well as a novel NG2-CreERT2 knockin mouse line. Thereby, we revealed the wide differentiation potential of NG2-glia. In a context-dependent fashion as given by development or injury processes, NG2 glia can generate oligodendrocytes, astrocytes or even neurons in vivo. |
