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Developmental biology - Brain Nerve Cells

Glutamate Stimulates Nerve Growth

Glutamate receptors affect development of brain cells...


Whenever we learn or save information, so-called ionotropic glutamate receptors play a crucial role in the process. These receptors are proteins located in the membrane of nerve cells that bind to the neurotransmitter glutamate. Glutamate causes excitation of the nerve cell, which transmits that excited state as a signal to its neighbors.

A subgroup of glutamate receptors, kainate receptors, are known to help regulate neuronal networks. Now, researchers at Ruhr-Universität Bochum (RUB) in Germany have discovered that these kainate receptors also affect the way nerve cells develop immediately following birth.

The research was headed by Alexander Jack PhD and Professor Petra Wahle from the Developmental Neurobiology research group, publishing their findings in the journal Molecular Neurobiology.

Cell activity affects dendrite growth

For their experiments, researchers used cells from the visual cortex of rats, adding small doses of kainic acid to cultures grown in their lab. "We observed that at a very early stage it caused cells to become much more active," explained Jack.
This increase in kainic acid activity affected the growth of a particular group of neurons called pyramidal cells. Pyramidal cells began growing more extensions that specialised in receiving signals and spread from the cell body towards the cerebral cortex.

human cerebral cortex


"We wondered which variant of the receptor is responsible for this phenomenon," says Jack. Subsequent experiments focused on the GluK2 subunit as the main suspect. GluK2 has long been known to affect the excitation of individual neurons and, as a result, to regulate the overall activity of entire networks.

Novel Research Approach

In the adult brain, these functions are crucial to higher cognitive function. "Not much research had been conducted to determine the role GluK2 plays in early maturation of nerve cells," explains Jack. Researchers then caused the nerve cells to produce greater amounts of the kainate receptor subunit GluK2, and observed how these manipulated cells became considerably more active earlier than typically expected. They also increased their dendrite growth.

Overall, researchers successfully tested a naturally occurring protein involved in the regulation of GluK2: tau tubulin kinase 2 (TTBK2). TTBK2 causes kainate receptors with a GluK2 subunit to be transported from the nerve cell membrane to within the cell where they cannot function. This is how the body can prevent excessive excitation of too many nerve cells.
Humans with a mutated TTBK2 protein suffer a motor disorder spinocerebellar ataxia type 11. It occurs from over-excitation in the spinocerebellum, within the cerebellum, causing neurons to die.
human brain cerebellum

In experiments conducted by Ruhr Universität Bochum biologists, overproduction of TTBK2 reduced neuronal excitation and branching of nerves - the exact opposite of effects triggered following enrichment of the GluK2 receptor.

Abstract
During neuronal development, AMPA receptors (AMPARs) and NMDA receptors (NMDARs) are important for neuronal differentiation. Kainate receptors (KARs) are closely related to AMPARs and involved in the regulation of cortical network activity. However, their role for neurite growth and differentiation of cortical neurons is unclear. Here, we used KAR agonists and overexpression of selected KAR subunits and their auxiliary neuropilin and tolloid-like proteins, NETOs, to investigate their influence on dendritic growth and network activity in organotypic cultures of rat visual cortex. Kainate at 500 nM enhanced network activity and promoted development of dendrites in layer II/III pyramidal cells, but not interneurons. GluK2 overexpression promoted dendritic growth in pyramidal cells and interneurons. GluK2 transfectants were highly active and acted as drivers for network activity. GluK1 and NETO1 specifically promoted dendritic growth of interneurons. Our study provides new insights for the roles of KARs and NETOs in the morphological and physiological development of the visual cortex.

Authors
Alexander Jack, Mohammad I. K. Hamad, Steffen Gonda, Sebastian Gralla, Steffen Pahl, Michael Hollmann and Petra Wahle.


Acknowledgements
The project was funded by the German Research Foundation (no. WA 541/9-1 no. 541/9-2) and by the foundation Wilhelm und Günter Esser-Stiftung.


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Dec 11, 2018   Fetal Timeline   Maternal Timeline   News   News Archive




Rat pyramidal cell. Image: Research Gate.


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