GABA and Plasticity—Can Antagonists Improve Cognition?

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using the GABAA antagonist pentylenetetrazole (PTZ), which was once used to treat heart conditions but has since been superseded by more effective, safer drugs.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

Comments

  1. I'd like to put forward the hypothesis that Aβ may compete with pleiotrophin (heparin-binding growth associated molecule) for binding to VEGF165. Yang and colleagues (1) report that binding of Aβ to VEGF165 inhibits both Aβ-induced formation of reactive oxygen species and Aβ aggregation. Pleiotrophin is found to be upregulated on PTEN depletion and also enhances GABAA signaling (2,3). In view of the fact that presenilin-deficient cells and AD brain have reduced PTEN levels and pleiotrophin is found in amyloid plaques in AD and DS (4,5), it would seem we may expect amyloid deposition and enhanced GABAA signaling in both disease states. The study by Craig Garner and colleagues reporting normal cognition in their mouse model following the use of GABAA antagonists is most interesting and would seem to indicate benefit for those with AD as well. It will be interesting to see the results of the clinical trials. Perhaps the study by Nabekura et al. finding that DHA inhibits the GABA response may help to explain the cognitive benefit reported by Cole and Frautschy (6,7).

    Increased pleiotrophin is also reported in multiple myeloma (8). Should my hypothesis be correct, then you'd expect an increased incidence of dementia and AD associated with that disease. Maybe GABAA inhibition is also indicated with possible silencing of pleiotrophin as a first step.

    It's interesting that the Forkhead transcription factors FKHRL1 and FKHR are aberrantly localized to the cytoplasm and cannot activate transcription in PTEN-deficient cells and that inactivation of Rho/ROCK signaling is a prerequisite for FKHR nuclear translocation and myoblast fusion (9,10). This may explain part of the benefit of ROCK inhibition. Is incomplete myoblast fusion a feature of AD, and if so, may it explain the gait abnormalities? It's of interest that DYRK1A, which is upregulated in AD brain, phosphorylates tau and also FKHR and reduces FKHR accumulation in the nucleus (10,11).

    References:

    Yang SP, Kwon BO, Gho YS, Chae CB. Specific interaction of VEGF165 with beta-amyloid, and its protective effect on beta-amyloid-induced neurotoxicity. J Neurochem. 2005 Apr;93(1):118-27. PubMed.

    Li G, Hu Y, Huo Y, Liu M, Freeman D, Gao J, Liu X, Wu DC, Wu H. PTEN deletion leads to up-regulation of a secreted growth factor pleiotrophin. J Biol Chem. 2006 Apr 21;281(16):10663-8. PubMed.

    Pavlov I, Rauvala H, Taira T. Enhanced hippocampal GABAergic inhibition in mice overexpressing heparin-binding growth-associated molecule. Neuroscience. 2006 May 12;139(2):505-11. PubMed.

    Zhang H, Liu R, Wang R, Hong S, Xu H, Zhang YW. Presenilins regulate the cellular level of the tumor suppressor PTEN. Neurobiol Aging. 2008 May;29(5):653-60. PubMed.

    Wisniewski T, Lalowski M, Baumann M, Rauvala H, Raulo E, Nolo R, Frangione B. HB-GAM is a cytokine present in Alzheimer's and Down's syndrome lesions. Neuroreport. 1996 Jan 31;7(2):667-71. PubMed.

    Nabekura J, Noguchi K, Witt MR, Nielsen M, Akaike N. Functional modulation of human recombinant gamma-aminobutyric acid type A receptor by docosahexaenoic acid. J Biol Chem. 1998 May 1;273(18):11056-61. PubMed.

    Cole GM, Frautschy SA. Docosahexaenoic acid protects from amyloid and dendritic pathology in an Alzheimer's disease mouse model. Nutr Health. 2006;18(3):249-59. PubMed.

    Yeh HS, Chen H, Manyak SJ, Swift RA, Campbell RA, Wang C, Li M, Lee HJ, Waterman G, Gordon MS, Ma J, Bonavida B, Berenson JR. Serum pleiotrophin levels are elevated in multiple myeloma patients and correlate with disease status. Br J Haematol. 2006 Jun;133(5):526-9. PubMed.

    Nakamura N, Ramaswamy S, Vazquez F, Signoretti S, Loda M, Sellers WR. Forkhead transcription factors are critical effectors of cell death and cell cycle arrest downstream of PTEN. Mol Cell Biol. 2000 Dec;20(23):8969-82. PubMed.

    Woods YL, Rena G, Morrice N, Barthel A, Becker W, Guo S, Unterman TG, Cohen P. The kinase DYRK1A phosphorylates the transcription factor FKHR at Ser329 in vitro, a novel in vivo phosphorylation site. Biochem J. 2001 May 1;355(Pt 3):597-607. PubMed.

    Kimura R, Kamino K, Yamamoto M, Nuripa A, Kida T, Kazui H, Hashimoto R, Tanaka T, Kudo T, Yamagata H, Tabara Y, Miki T, Akatsu H, Kosaka K, Funakoshi E, Nishitomi K, Sakaguchi G, Kato A, Hattori H, Uema T, Takeda M. The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between beta-amyloid production and tau phosphorylation in Alzheimer disease. Hum Mol Genet. 2007 Jan 1;16(1):15-23. PubMed.

    View all comments by Mary Reid

  2. It's of interest that Zhao and colleagues (1) found increased efflux of thiamine pyrophosphate in leukemia cells overexpressing the reduced folate carrier. The possibility of reduced cellular thiamine pyrophosphate in DS due to the overexpression of RFC1 is very intriguing. Dodd et al. (2) find increased GABAA and reduced NMDA binding sites in some brain areas in a goat model with thiamine deficiency. It would be interesting to see whether administration of thiamine pyrophosphate in the mouse model of DS would restore cognition as do the GABAA antagonists in the Garner study. Thiamine deficiency has been described as a rare cause of reversible pulmonary hypertension and it makes me wonder whether that might explain the increased risk of this disease as well as congenital ASD and VSD in the DS population (3).

    References:

    Zhao R, Gao F, Wang Y, Diaz GA, Gelb BD, Goldman ID. Impact of the reduced folate carrier on the accumulation of active thiamin metabolites in murine leukemia cells. J Biol Chem. 2001 Jan 12;276(2):1114-8. PubMed.

    Dodd PR, Thomas GJ, McCloskey A, Crane DI, Smith ID. The neurochemical pathology of thiamine deficiency: GABAA and glutamateNMDA receptor binding sites in a goat model. Metab Brain Dis. 1996 Mar;11(1):39-54. PubMed.

    Park JH, Lee JH, Jeong JO, Seong IW, Choi SW. Thiamine deficiency as a rare cause of reversible severe pulmonary hypertension. Int J Cardiol. 2007 Sep 14;121(1):e1-3. PubMed.

    View all comments by Mary Reid

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References

News Citations

  1. Memory Enhancement: Two Drugs Better Than One?—Plus, γ-secretase Inhibitor Update

Paper Citations

  1. Dekosky ST, Fitzpatrick A, Ives DG, Saxton J, Williamson J, Lopez OL, Burke G, Fried L, Kuller LH, Robbins J, Tracy R, Woolard N, Dunn L, Kronmal R, Nahin R, Furberg C, . The Ginkgo Evaluation of Memory (GEM) study: design and baseline data of a randomized trial of Ginkgo biloba extract in prevention of dementia. Contemp Clin Trials. 2006 Jun;27(3):238-53. PubMed.
  2. ANDOSCA JB. Effects of pentylenetrazol on senile patients; a clinical study. N Engl J Med. 1954 Mar 18;250(11):461-3. PubMed.

Further Reading

Primary Papers

  1. 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. Nat Neurosci. 2007 Apr;10(4):411-3. PubMed.

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