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Down Syndrome Abstract
of the Month: Apr 2007

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Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome

Fernandez F, Morishita W, Zuniga E, Nguyen J, Blank M, Malenka RC, Garner CC.
Nature Neurosci. 2007 Apr;10(4):411-3.

Department of Psychiatry and Behavioral Sciences, Nancy Pritzker Laboratory, Stanford University, Palo Alto, California

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Ts65Dn mice, a model for Down syndrome, have excessive inhibition in the dentate gyrus, a condition that could compromise synaptic plasticity and mnemonic processing. We show that chronic systemic treatment of these mice with GABA(A) antagonists at non-epileptic doses causes a persistent post-drug recovery of cognition and long-term potentiation. These results suggest that over-inhibition contributes to intellectual disabilities associated with Down syndrome and that GABA(A) antagonists may be useful therapeutic agents for this disorder.

My comments:

Such a small abstract with such a large impact. This is the study that created so many headlines worldwide a couple of months ago. We'll need to review a few things of mice and men before we consider what this study actually found.

Since it's so hard to study actual brain cells from people with Down syndrome, the research community has settled on mice to research as a model for DS. The current model, named the Ts65Dn strain, is the best so far at having the mouse version of most (not all) of the chromosomes found on the human 21st chromosome, and living long enough to be useful in experiments. Living Ts65Dn mice have cognitive difficulties as well as abnormalities of organ systems similar to those found in people with DS, making them very useful.

As far back as 1995, researchers found that the Ts65Dn mouse had impaired memory and learning. Since the hippocampus is the part of the brain closely associated with learning, research has been done on the brain cells found in that specific area. In 2004, a group from Stanford studied Ts65Dn hippocampal brain cells grown outside of the body and found that the transmission of nerve impulses from one brain cell to the next was impaired in these mice, due to increased inhibition of the brain cells by a neurochemical called GABA.(1) They then theorized that learning difficulties in these mice might be due to this increased inhibition, and speculated this would also be true for people with DS as well.

For parents not familiar with neuroscience, brain cells (or more specifically, a type of brain cell called a "neuron,") use neurotransmitters to affect the neurons around them. The neurons produce these neurotransmitters and when stimulated, release them into the small gap, or synapse, between the neurons. These neurotransmitters attach to small structures on the outside of neurons called "receptors" that allow them to have an effect on the membrane of the neuron. By making small changes in the neuron's membrane, the neurotransmitters either: stimulate, or cause surrounding neurons to fire; or inhibit, or cause the neurons from firing. Which of these two actions occurs depends on whether the neurotransmitter is excitatory or inhibitory. GABA is the main inhibitory transmitter in the brain, and is useful to tell brains cells to stop firing when they are no longer needed. However, too much inhibition is not a good thing.

Back to the 2004 study. Picrotoxin is a chemical that prevents GABA from inhibiting the neuron by taking up space on the GABA receptors but not having any GABA-like activity on the neuron. This is called a GABA "antagonist" chemical. The researchers used picrotoxin to eliminate the GABA inhibition of the Ts65Dn neurons, and found that the neurons were capable then of normal function.

Now on to the current study. The researchers wanted to see what effect a GABA antagonist drug might have on living Ts65Dn mice. First, it was established that the Ts65Dn mice had a problem discriminating a new object from a familiar object in their environment. (Normal mice spend a lot more time examining unfamilair objects than familiar objects.) Then, picrotoxin was injected into the mice one time. This had no observed effect. Next, the mice were injected with either picrotoxin or saline for 2 weeks. The picrotoxin-injected mice behaved like regular mice in the object discrimination test while the saline-injected mice had no change. As an addition benefit, the mice that received the picrotoxin continued the normal behavior two weeks after the injections were stopped.

Next, the researchers carried out the same test with oral pentylenetetrazole (PTZ), another GABA antagonist drug. Ts65Dn mice given PTZ in milk developed normal learning behavior after 17 days. The same mice were re-evaluated 2 months after the PTZ was stopped, and still showed normal learning behavior.

The importance of this study is that if the neurons of children with DS are similar to those in the trisomy mice, then it may be possible to use a GABA blocking drug to improve learning in children with DS. However, it is also important to note that in the past, drugs that helped learning in mice haven't translated well to humans. The Stanford research group appears to be working hard to get permission to test PTZ out on humans, but this may be a few years in the future before we know anymore.

Postscript: On the basis of this research, many parents of children with DS have expressed an interest in the herb ginkgo biloba, as the compound bilobalide found in this herb is a GABA antagonist. I'll be writing a separate essay on the use of ginkgo in people with DS.

1. Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome. Kleschevnikov AM, Belichenko PV, Villar AJ, Epstein CJ, Malenka RC, Mobley WC. J Neurosci. 2004 Sep 15;24(37):8153-60.
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