5 March 2007. Boosting neuronal excitation with acetylcholinesterase inhibitors is one way of tackling cognitive decline in Alzheimer disease (AD). Might suppressing inhibitory neurons be another? In the February 25 Nature Neuroscience online, Craig Garner and colleagues at Stanford University, Palo Alto, California, report that blocking inhibitory GABA signals can reverse cognitive deficits in a mouse model of Down syndrome. GABA antagonists are currently in clinical trials for Alzheimer disease. Though the mice used in this study have no pathological signs of AD, they, like Down syndrome patients, have a triplication of a large chromosome section that harbors the amyloid-β precursor protein (APP, on chromosome 16 in mice, 21 in humans). While it is unclear what role APP plays in Down syndrome, that GABA antagonists help reverse cognitive losses in the mouse model suggests that they may also benefit Down syndrome patients and perhaps even AD patients.
GABA (γ-amino butyric acid) is the major inhibitory neurotransmitter in the brain. Studies suggest that it can suppress long-term potentiation, a form of neuronal plasticity essential for learning and memory. To test if that might explain cognitive deficits in the Ts65Dn mouse, first author Fabian Fernandez and colleagues administered various GABAA receptor antagonists to the animals. They found that when given either picrotoxin or bilobalide—one of the active ingredients in Gingko biloba extracts—the Ts65Dn Down’s mice performed just as well as normal mice in a novel object recognition test. The researchers extended the study using the GABAA antagonist pentylenetetrazole (PTZ), which was once used to treat heart conditions but has since been superseded by more effective, safer drugs. The Ts65Dn mice given PTZ performed just as well as controls in the novel object recognition test and also in a spontaneous alternation task using a T-maze.
Exactly how the GABA antagonists protect these mice from cognitive losses is not entirely clear. It is not simply a matter of reducing inhibitory neuronal inputs, because acute treatment had no effect. Mice had to be given the drugs over several weeks before their cognitive abilities rivaled that of control animals. In addition, the cognitive improvements lasted as long as 2 months after the drug treatment ended, indicating that the drugs had some long-lasting effect in the brain. Garner believes that chronic low doses of drugs induced some form of long-term change into the neural circuitry.
“Acute doses of GABA inhibitors clearly don’t work. We think you have to treat over a period of time with a once-a-day dose. What this does is lead to a transient increase in excitation, and the brain does something called ‘adaptive change’ where it basically takes this new information and is able to suppress, with time, the inhibitory load and come to a new state in which the inhibition is now overcome and the excitatory circuits are now able to function in a more natural setting,” Garner told ARF. He believes that the adaptive change in these mice is similar to the changes elicited in humans taking antidepressants such as serotonin reuptake inhibitors. These drugs do not work right away, but once they do they can often be withdrawn, at least temporarily, because the brain has learned to compensate. “We think that it is that mechanism we are tapping into,” said Garner.
Such adaptive change would likely involve synaptic rearrangements. Indeed, Fernandez and colleagues found that the GABA antagonists rescued long-term potentiation in dentate gyrus cells of the Ts65Dn mice. The dentate gyrus of the hippocampus plays an important role in learning and memory.
Whether GABA antagonists will eventually be used to treat Down syndrome patients remains to be seen. One such drug, SGS742, is currently in clinical trials for Alzheimer disease (see ARF related news story) and the Ginkgo Evaluation of Memory trial is currently ongoing for AD patients, as well (see DeKosky et al., 2006). “Our study doesn’t directly apply to Alzheimer’s, but the mechanism that we have tapped into is clearly a potential target. However, there may be an age-dependency, in that in early stages it may have more beneficial effect but not as disease progresses,” said Garner. The cognitive properties of PTZ were tested in senile patients in the 1950s (see, e.g., Andosca, 1954). “Though there was evidence that some people did better on PTZ, overall it was deemed not to have any significant effect,” said Garner. He also noted that the dosing regimen used in those studies would not have been conducive to adaptive change, suggesting this drug and/or other GABA antagonists may be worthy of further study.—Tom Fagan.
Fernandez F, Morishita W, Zuniga E, Nguyen J, Blank M, Malenka RC, Garner CC. Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nature Neuroscience. 2007 Feb 25. Advanced Online Publication. Abstract