Nervous Inhibitions

How inhibitory signal transmission between nerve cells affects development

May 29, 2006

A computer - or any digital system which processes and stores information - knows only two states: "on" and "off". While our brain may not be a computer, the signals of nerve cells can also represent "on" or "off" states, causing the receiving - "post-synaptic" - cells to either propagate the signal or to terminate signal transmission. The orchestrated interplay of stimulating and inhibitory signals is central to the development and functioning of the entire nervous system. If inhibitory neurons are prevented from carrying out their function, this causes major defects early in embryonal development - and these defects can even occur outside the nervous system. These are the results of a study recently published by scientists from the Max Planck Institute for Experimental Medicine in Göttingen (Neuron, May 18, 2006).

Nerve cells from the spinal cord of VIAAT mouse mutants. The yellow dots indicate structurally intact synapses between nerve cells. They develop normally in the absence of GABA and glycine release - contrary to the generally accepted view.

The most common inhibitory transmitters in the mammalian central nervous system are GABA and glycine. Nerve cells can release GABA or glycine where they contact other nerve cells at junctions called synapses. This typically prevents further signal transmission by the post-synaptic cell.

Most inhibitory nerve cells release either GABA or glycine. However, some inhibitory nerve cells appear to be "bilingual", releasing a mixture of GABA and glycine. These mixed-release cells are most common during nervous system development and seem to be crucial for normal spinal cord growth. For brain researchers, however, they have proven mysterious. Most nerve cells specialise in releasing only one type of neurotransmitter. They use transport proteins to pump the neurotransmitter into vesicles surrounded by a membrane and store it there until release is triggered.

Sonja Wojcik and Jeong-Seop Rhee, from the Department of Molecular Neurobiology at the Max Planck Institute for Experimental Medicine in Göttingen, Germany, working with colleagues from Kaiserslautern, Germany and Houston, Texas, have discovered what enables nerve cells to release both GABA and glycine. The researchers discovered that one particular transport protein called VIAAT is able to store both GABA and glycine in vesicles; this joint storage is rather unusual for a classical neurotransmitter. The scientists genetically altered mice so that their nerve cells do not produce VIAAT. This change eliminated both GABA and glycine release.

The scientists did not just solve the problem of simultaneous release of GABA and glycine from "bilingual" spinal cord nerve cells. They also disproved a piece of textbook wisdom, that release of GABA from nerve cells is important for their growth and maturation. The commonly held view was that without releasing GABA, nerve cells remain in an immature state and cannot form intact synapses with one another. Wojcik and Rhee refute this dogma. Their research on VIAAT mutant mice shows that nerve cells develop relatively normally and build structurally intact synapses, even when GABA and glycine release is completely eliminated.

The brain, however, cannot function without GABA and glycine release. Mice without VIAAT are completely unable to move, and have two noticeable defects: a cleft palate, and an umbilical hernia, whereby the intestine stays outside the abdominal cavity, in the umbilical cord. For both of these developmental problems - which are fairly common in humans - the fact that the mutant mice are paralysed is most likely a major contributing factor. However, at least in the case of the hernia, the lack of GABA and glycine also appears to have a more direct effect. Other mutations, which prevent a normal function of GABA and glycine, also cause such a hernia. Sonja Wojcik says, "faulty inhibitory nerve signal transmission can be a reason for defective embryonal intestinal development." It is still unclear, however, how these results could be applied therapeutically.

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