Juggling molecules while balancing the brain

Research highlight from the MDC
(visit www.mdc-berlin.de to see more highlights from MDC research)

People with a mental illness are sometimes described as being “unbalanced” or “having a screw loose.” These expressions may not be very polite, but they capture two important aspects of mental and physical health. First, organs such as the brain need to maintain an overall balance as we experience stress and engage in various types of activity. Ultimately this state depends on the functions of fundamental components in our cells – not screws, of course, but proteins and other molecules. A frenetic activity at this vastly smaller scale is required to ensure the stability of cells and tissues. While it is often extremely difficult to connect these levels of biological structure, the lab of Jochen Meier has established a new link. In a recent study in the Journal of Clinical Investigation, the group has connected a molecule called the glycine receptor (GlyR) to the operation of networks of neurons – and the way they are disrupted in epilepsy.

Jochen and his colleagues had already found an association between GlyR and brain disorders. They had carried out a molecular analysis of brain tissue from epilepsy patients. This disease is caused by an overexcitation of certain neurons, particularly in a region of the brain called the hippocampus. “We found that hippocampal cells produce unusually high proportions of a specific form of GlyR,” Jochen says. “The current project aimed to show how this molecule contributes to higher brain functions and eventually causes symptoms related to the disease.”

GlyR has one function that is clearly related to signal transmission between brain cells: it acts as a receptor for a neurotransmitter called glycine. Neurons release neurotransmitters into synapses, tiny gaps that separate them from their neighbors. These small molecules typically dock onto receptor proteins on other cells (postsynaptic) or on presynaptic receptors of the original cell. Depending on the type of neurotransmitter receptor and type of neuron, this either inhibits or promotes the signal.

The GlyR can be composed of two different proteins called alpha and beta subunits. Our genome encodes only one beta protein, but cells pick and choose between different genes for the alpha subunit. It may be combined with the beta subunit to create the GlyR; however, single cells sometimes produce GlyRs composed of alpha subunits only.

Like all proteins, the GlyR alpha3 subunit (GlyR-a3) is produced when the information in its gene is transcribed into an RNA molecule. Later the RNA is translated into protein. Along the way bits and pieces of the RNA may be removed in a process called splicing, creating proteins of different lengths, containing different functional modules – a bit like adding or removing wagons from a train.

GlyR-a3 RNA sometimes undergoes yet another change that affects its chemistry and functions. During a process called RNA editing, one letter of the molecule is swapped for another. This causes a corresponding change in the chemistry of GlyR-a3 protein and makes it work more efficiently. What Jochen’s team had discovered in epilepsy patients was an unusually high proportion of “long” spliced forms, and they also observed a swap in one letter of its chemical alphabet.

GlyR-a3 is known to inhibit the firing of neurons in the spinal cord, which can block the transmission of signals related to pain. This might mean that the form of GlyR-a3 found by Jochen’s team (the long spliced form, changed by RNA editing) was tuning down the excitability of neural networks in epileptic patients. To find out, the lab needed to observe the behavior of the altered molecule in an animal’s brain. Aline Winkelmann and other members of Jochen’s lab developed a strain of mouse in which particular cells in the hippocampus – called glutamatergic excitatory neurons – produce high amounts of this version of GlyR-a3.

Now they measured the way the change affected the animals in various ways: checking whether it affected the structure of neurons, the excitability of neural networks, cognition, memory, and mood-related behavior. Unexpectedly, they discovered that the altered form of GlyR-a3 caused an overexcitation of the system – and an important reason why.

“The long spliced form of GlyR-a3 is packed up with presynaptic vesicles,” Jochen says. “These are bubble-like packages that neurotransmitters are placed into before cells release them. Put this association together with an increased sensitivity to the neurotransmitter – and even some spontaneous activity due to the change in the receptor’s chemistry – and the neurons were prone to release more neurotransmitters. This had measurable effects on behavior: it disturbed the animals’ cognitive functions and some forms of memory.”

The study yielded another extremely interesting and wholly unexpected finding. The scientists discovered that in another type of cell, parvalbumin-positive inhibitory interneurons, higher amounts of the molecule had completely different effects on network excitability and behavior.
“Here the result was reduced network excitability, because it was enhancing the functions of this type of neuron,” Jochen says. “The change triggered anxiety-related behavior in the animals. But it did not cause any changes in cognitive function.”

A close scrutiny of the animals’ neurons and hippocampus didn’t reveal any significant changes in overall structure. In other words, higher amounts of this form of the GlyR-a3 molecule weren’t “rewiring” the animals’ brain network. Instead, they were persistently changing the overall balance of neural networks by enhancing the neuronal output.

“What we’ve done is to identify a mechanism at the level of molecules that is linked to the release of neurotransmitters and identifies two critical types of neurons that can cause an imbalance in the brain,” Jochen says. “We think this helps explain both changes in excitability of the brain network in epilepsy and the neuropsychiatric symptoms of some types of anxiety that are often associated with the disease.”

– Russ Hodge

Reference:

Winkelmann A, Maggio N, Eller J, Caliskan G, Semtner M, Häussler U, Jüttner R, Dugladze T, Smolinsky B, Kowalczyk S, Chronowska E, Schwarz G, Rathjen FG, Rechavi G, Haas CA, Kulik A, Gloveli T, Heinemann U, Meier JC. Changes in neural network homeostasis trigger neuropsychiatric symptoms. J Clin Invest. 2014 Feb 3;124(2):696-711.

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