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A Molecule for Proper Neural Wiring in the Cerebellum

Summary: Researchers reveal the role GLAST plays in establishing and maintaining neural wiring of Purkinje cells.

Source: Hokkaido University.

A molecule produced by insulating glial cells facilitates the functional wiring of brain cells involved in motor coordination.

Researchers at Hokkaido University have found that the molecule “L-gutamate/L-aspartate transporter” (GLAST) plays an essential role in establishing and maintaining proper neural wiring of Purkinje cells in the cerebellum.

Purkinje cells are among the largest nerve cells in the brain. They are present in the cerebellum, a small structure in the back of the brain influencing motor coordination. They are mainly hooked up to the nervous system by means of two distinct types of nerve fibers, “parallel fibers” and “climbing fibers.” Those fibers connect to different part of Purkinje cell dendrites, or the branches projecting from the cell body, segregating their territories.

GLAST is a molecule produced by specialized insulating cells, called Bergmann glia, that wrap around Purkinje cell synapses (a synapse is the structure connecting one nerve cell to another). GLAST’s role is to remove excess glutamate, a neurotransmitter used by parallel and climbing fibers to send signals to Purkinje cells. This facilitates a “high-fidelity” signal, by allowing the right amount of glutamate to reach the targeted nerve cell without spilling over onto its neighbors. However, little is known about GLAST’s role in the development of neural circuits.

Professor Masahiko Watanabe of Hokkaido University and his colleagues in Japan compared the wiring of Purkinje cells in normal mice and mutant mice lacking GLAST. The wiring of Purkinje cells in the mutant mice was laden with abnormalities.

Each Purkinje cell is normally innervated by a single climbing fiber as a result of competition between the fibers during development. However, in the mutant mice, Purkinje cells were innervated by multiple climbing fibers, which apparently caused the Purkinje cells to be atypically excited.

Image shows Purkinje cells.

In the normal mice (left panel), connections between Purkinje cells (asterisks) and climbing fibers or parallel fibers are thoroughly wrapped by Bergmann glia (colored in red), whereas they are exposed to their neighbors in the knockout mice lacking GLAST (right panel, arrowheads). NeuroscienceNews.com image is credited to Miyazaki T. et al./PNAS.

Parallel fibers were also affected. They robustly increased the number of connections with Purkinje cells, impairing the territorial segregation between climbing fibers and parallel fibers. Furthermore, in the knockout mice, Bergmann glial cells were improperly wrapped around the Purkinje cells, exposing them to the external environment.

In a different experiment, they also found that functional blockade of GLAST in normal adult mice results in similar abnormalities as seen in the knockout mice.

“We have shown that the glutamate transporter, GLAST, plays important roles in establishing and maintaining proper nerve wiring and insulation in the cerebellum. Further investigation should reveal how GLAST’s function is related to the plasticity of the neural network,” says Masahiko Watanabe.

About this neuroscience research article

Funding: Ministry of Education, Culture, Sports, Science and Technology of Japan funded this study.

Source: Naoki Namba – Hokkaido University
Image Source: NeuroscienceNews.com image is credited to Miyazaki T. et al./PNAS.
Original Research: Abstract for “Glutamate transporter GLAST controls synaptic wrapping by Bergmann glia and ensures proper wiring of Purkinje cells” by Taisuke Miyazaki, Miwako Yamasaki, Kouichi Hashimoto, Kazuhisa Kohda, Michisuke Yuzaki, Keiko Shimamoto, Kohichi Tanaka, Masanobu Kano, and Masahiko Watanabe in PNAS. Published online July 27 2017 doi:10.1073/pnas.1617330114

Cite This NeuroscienceNews.com Article
Hokkaido University “A Molecule for Proper Neural Wiring in the Cerebellum.” NeuroscienceNews. NeuroscienceNews, 28 July 2017.
<http://neurosciencenews.com/cerebellum-neural-wiring-7199/>.
Hokkaido University (2017, July 28). A Molecule for Proper Neural Wiring in the Cerebellum. NeuroscienceNew. Retrieved July 28, 2017 from http://neurosciencenews.com/cerebellum-neural-wiring-7199/
Hokkaido University “A Molecule for Proper Neural Wiring in the Cerebellum.” http://neurosciencenews.com/cerebellum-neural-wiring-7199/ (accessed July 28, 2017).

Abstract

Glutamate transporter GLAST controls synaptic wrapping by Bergmann glia and ensures proper wiring of Purkinje cells

Astrocytes regulate synaptic transmission through controlling neurotransmitter concentrations around synapses. Little is known, however, about their roles in neural circuit development. Here we report that Bergmann glia (BG), specialized cerebellar astrocytes that thoroughly enwrap Purkinje cells (PCs), are essential for synaptic organization in PCs through the action of the L-glutamate/L-aspartate transporter (GLAST). In GLAST-knockout mice, dendritic innervation by the main ascending climbing fiber (CF) branch was significantly weakened, whereas the transverse branch, which is thin and nonsynaptogenic in control mice, was transformed into thick and synaptogenic branches. Both types of CF branches frequently produced aberrant wiring to proximal and distal dendrites, causing multiple CF–PC innervation. Our electrophysiological analysis revealed that slow and small CF-evoked excitatory postsynaptic currents (EPSCs) were recorded from almost all PCs in GLAST-knockout mice. These atypical CF-EPSCs were far more numerous and had significantly faster 10–90% rise time than those elicited by glutamate spillover under pharmacological blockade of glial glutamate transporters. Innervation by parallel fibers (PFs) was also affected. PF synapses were robustly increased in the entire dendritic trees, leading to impaired segregation of CF and PF territories. Furthermore, lamellate BG processes were retracted from PC dendrites and synapses, leading to the exposure of these neuronal elements to the extracellular milieus. These synaptic and glial phenotypes were reproduced in wild-type mice after functional blockade of glial glutamate transporters. These findings highlight that glutamate transporter function by GLAST on BG plays important roles in development and maintenance of proper synaptic wiring and wrapping in PCs.

“Glutamate transporter GLAST controls synaptic wrapping by Bergmann glia and ensures proper wiring of Purkinje cells” by Taisuke Miyazaki, Miwako Yamasaki, Kouichi Hashimoto, Kazuhisa Kohda, Michisuke Yuzaki, Keiko Shimamoto, Kohichi Tanaka, Masanobu Kano, and Masahiko Watanabe in PNAS. Published online July 27 2017 doi:10.1073/pnas.1617330114

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