07 Oct 2011

KIBRA has been linked to human memory, but it hasn't been clear how this protein works in the brain. Two recent studies take steps to clarify its function in memory processes. One confirms that KIBRA supports episodic memory in humans, and hints that a genetic variant heightens hippocampal activation in aging. The other suggests that KIBRA protects memory in mice, perhaps by regulating AMPA receptor trafficking and synaptic plasticity. Together, the papers strengthen the notion that KIBRA plays a role in memory and provides a possible mechanism for its function.

Researchers first discovered KIBRA in connection with human memory in a 2006 genomewide screen (see ARF related news story on Papassotiropoulos et al., 2006). The name KIBRA stems from the protein's expression both in the kidney and in the brain. Led by Andreas Papassotiropoulos at the University of Basel, Switzerland, that study pinpointed a single nucleotide polymorphism—a thymine (T) in place of a cytosine (C)—that correlated with better episodic memory. In the same study, researchers noted that young T carriers have less hippocampal activation than performance-matched non-T carriers. The researchers interpreted that to mean that T carriers had to work less hard to achieve the same level of performance as non-T carriers.

Now, in the October 5 Journal of Neuroscience, Lars Nyberg, Umea University, Sweden, and colleagues confirm that T allele carriers outperformed non-carriers on an episodic memory task. However, they activated their hippocampi more. The research team, including first author Karolina Kauppi, tested 2,230 cognitively normal people aged 35-85 on word recall. KIBRA T carriers performed better than their age- and sex-matched non-carrier counterparts. In a separate functional magnetic resonance imaging study of 83 people aged 55-60, T carriers had increased hippocampal activation during the episodic memory task, relative to their non-T carrier counterparts, which is in direct contrast to Papassotiropoulos’ findings. The reason for the discrepancy is unclear, Kauppi and colleagues write. It could have to do with the age of the test populations (the previous study tested 22- to 23-year-olds). Kauppi and colleagues also used a slightly more demanding memory task, and a larger sample size, which has more statistical power.

More hippocampal activation would fit better with the better memory performance, said Kauppi. "For most studies, it's quite well accepted that increased activation in the hippocampus is related to improved memory in many different ways—you have longer duration of your memory, and its stronger and more vivid than if you have decreased activation," she noted.

Papassotiropoulos is not sure why there's a difference in hippocampal activation between the two studies, but agreed that age and task differences between the two studies could be factors. Regardless of the difference, he said the important finding is that KIBRA strongly associates with episodic memory, and that genetic variations somehow alter hippocampal functioning. "We still don't have any idea what the consequence of the KIBRA polymorphism is at the molecular level," he added. "So in these circumstances, we need to be very cautious about mechanistic interpretations of imaging in genetics studies."

Clues about KIBRA’s molecular function come from the September 22 Neuron. Researchers led by Richard Huganir of the Johns Hopkins University School of Medicine in Baltimore, Maryland, propose that KIBRA regulates the movement of AMPA neurotransmitter receptors, which are essential for synaptic plasticity and learning. Huganir and colleagues isolated KIBRA about 10 years ago, before it had a name, when they found it bound to protein interacting with C-kinase 1 (PICK1). PICK1 maintains optimal numbers of AMPA receptors on the surface of neurons by inhibiting their reinsertion into the cell membrane—or recycling. When Huganir learned that KIBRA was implicated in human memory performance, he began to study what it did on the cellular level.

First authors Lauren Makuch and Lenora Volk immunoprecipitated KIBRA from mouse neurons and showed that, in addition to binding PICK1, it formed a complex with several other AMPAR regulators, hinting that KIBRA plays a role in AMPAR trafficking. The researchers then knocked down KIBRA by small hairpin RNAs and saw activity-dependent AMPAR recycling go up. This suggested that KIBRA, like PICK1, has to do with the activity-dependent recycling of AMPA receptors and synaptic plasticity. "The level of AMPA receptors has to be precisely controlled," said Volk. "Aberrant trafficking, one way or the other, impairs the ability to have normal plasticity."

That abnormal plasticity was evident in the KIBRA knockout mice the team created. While young knockout mice seemed normal, adult animals, though otherwise viable, exhibited deficits in hippocampal long-term potentiation and long-term depression. The older KIBRA knockouts more slowly learned to associate a foot shock with a tone, and more quickly forgot those associations. Taken together, the results link KIBRA to AMPAR trafficking and synaptic plasticity required for normal hippocampus-dependent learning in adult mice, the authors wrote.

"This suggests that in humans, that's what KIBRA is doing, too—regulating memory recall through regulating receptor trafficking and synaptic plasticity," said Huganir.

Since previous research found that non-T carriers have an increased risk of late-onset Alzheimer’s disease (see Corneveaux et al., 2010), altered AMPAR trafficking could be one reason for the cognitive deficits in AD patients, the authors wrote. The work suggests "that this gene is protecting against memory loss in late-onset AD by regulating receptor trafficking and synaptic plasticity," said Huganir.

Neither paper points to a potential treatment for Alzheimer‘s. For scientists who study KIBRA, "our ultimate goal is to identify druggable partners of KIBRA, which we can manipulate pharmacologically to see if we can enhance memory," Papassotiropoulos told ARF.—Gwyneth Zakaib

Comments

1. • Karolina Kauppi
     University of Umea
   • Posted: 07 Oct 2011
   • Paper: Regulation of AMPA receptor function by the human memory-associated gene KIBRA.

   I find it both interesting and important to reveal the molecular role of KIBRA in learning and memory. I would say that these findings are well in line with ours by showing that the role for KIBRA is mediated through an impact on learning and memory processes in the hippocampus. This strong molecular link to hippocampal processing strengthens our suggestion that the increased hippocampal activation seen in T carriers reflects improved hippocampal processing that actually mediates the increased memory performance of this group. It remains to be seen whether the polymorphism studied (rs17070145) is functional (although it is intronic), or in linkage disequilibrium with another polymorphism that is functional.

   View all comments by Karolina Kauppi
2. • Roberto Malinow
     University of California, San Diego
   • Posted: 07 Oct 2011

   Interesting papers. It's quite amazing that a protein linked to enhanced memory performance can be linked to synaptic plasticity, and AMPAR trafficking. The study by Makuch et al. provides more evidence that AMPA-R trafficking is an important regulated process in memory formation. Given that the T allele may provide some protection against AD, it supports a role for defects in AMPAR trafficking in AD. In this context it would be nice to know how the T allele changes AMPAR trafficking in model systems.

   View all comments by Roberto Malinow

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References

News Citations

1. Thanks for the Memories—KIBRA Alleles Predict Top Memory Performers 20 Oct 2006

Paper Citations

1. Papassotiropoulos A, Stephan DA, Huentelman MJ, Hoerndli FJ, Craig DW, Pearson JV, Huynh KD, Brunner F, Corneveaux J, Osborne D, Wollmer MA, Aerni A, Coluccia D, Hänggi J, Mondadori CR, Buchmann A, Reiman EM, Caselli RJ, Henke K, de Quervain DJ. Common Kibra alleles are associated with human memory performance. Science. 2006 Oct 20;314(5798):475-8. PubMed.
2. Corneveaux JJ, Liang WS, Reiman EM, Webster JA, Myers AJ, Zismann VL, Joshipura KD, Pearson JV, Hu-Lince D, Craig DW, Coon KD, Dunckley T, Bandy D, Lee W, Chen K, Beach TG, Mastroeni D, Grover A, Ravid R, Sando SB, Aasly JO, Heun R, Jessen F, Kölsch H, Rogers J, Hutton ML, Melquist S, Petersen RC, Alexander GE, Caselli RJ, Papassotiropoulos A, Stephan DA, Huentelman MJ. Evidence for an association between KIBRA and late-onset Alzheimer's disease. Neurobiol Aging. 2010 Jun;31(6):901-9. PubMed.

Further Reading

News

1. Thanks for the Memories—KIBRA Alleles Predict Top Memory Performers 20 Oct 2006