KIBRA: A New Gateway to Learning and Memory?
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ABSTRACT:
SUBMITTER: Schneider A
PROVIDER: S-EPMC2874402 | biostudies-literature | 2010
REPOSITORIES: biostudies-literature
Publications
KIBRA: A New Gateway to Learning and Memory?
Schneider Armin A Huentelman Matthew J MJ Kremerskothen Joachim J Duning Kerstin K Spoelgen Robert R Nikolich Karoly K
Frontiers in aging neuroscience 20100212
The genetic locus encoding KIBRA, a member of the WWC family of proteins, has recently been shown to be associated with human memory performance through genome-wide single nucleotide polymorphism screening. Gene expression analysis and a variety of functional studies have further indicated that such a role is biologically plausible for KIBRA. Here, we review the existing literature, illustrate connections between the different lines of evidence, and derive models based on KIBRA's function(s) in ...[more]
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Project description:The WWC1 gene has been genetically associated with human episodic memory performance, and its product KIdney/BRAin protein (KIBRA) has been shown to interact with the atypical protein kinase protein kinase M ? (PKM?). Although recently challenged, PKM? remains a candidate postsynaptic regulator of memory maintenance. Here, we show that PKM? is subject to rapid proteasomal degradation and that KIBRA is both necessary and sufficient to counteract this process, thus stabilizing the kinase and maintaining its function for a prolonged time. We define the binding sequence on KIBRA, a short amino acid motif near the C-terminus. Both hippocampal knock-down of KIBRA in rats and KIBRA knock-out in mice result in decreased learning and memory performance in spatial memory tasks supporting the notion that KIBRA is a player in episodic memory. Interestingly, decreased memory performance is accompanied by decreased PKM? protein levels. We speculate that the stabilization of synaptic PKM? protein levels by KIBRA may be one mechanism by which KIBRA acts in memory maintenance. KIBRA/WWC1 has been genetically associated with human episodic memory. KIBRA has been shown to be post-synaptically localized, but its function remained obscure. Here, we show that KIBRA shields PKM?, a kinase previously linked to memory maintenance, from proteasomal degradation via direct interaction. KIBRA levels in the rodent hippocampus correlate closely both to spatial memory performance in rodents and to PKM? levels. Our findings support a role for KIBRA in memory, and unveil a novel function for this protein.
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Project description:Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimer's disease (AD) and related tauopathies. Here, we define a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIdney/BRAin (KIBRA) protein (CT-KIBRA). We show that CT-KIBRA restores plasticity and memory in transgenic mice expressing pathogenic human tau; however, CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss. Instead, we find that CT-KIBRA binds to and stabilizes protein kinase Mζ (PKMζ) to maintain synaptic plasticity and memory despite tau-mediated pathogenesis. In humans we find that reduced KIBRA in brain and increased KIBRA in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. Thus, our results distinguish KIBRA both as a novel biomarker of synapse dysfunction in AD and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.
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Project description:KIBRA has recently been identified as a gene associated with human memory performance. Despite the elucidation of the role of KIBRA in several diverse processes in nonneuronal cells, the molecular function of KIBRA in neurons is unknown. We found that KIBRA directly binds to the protein interacting with C-kinase 1 (PICK1) and forms a complex with α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs), the major excitatory neurotransmitter receptors in the brain. KIBRA knockdown accelerates the rate of AMPAR recycling following N-methyl-D-aspartate receptor-induced internalization. Genetic deletion of KIBRA in mice impairs both long-term depression and long-term potentiation at hippocampal Schaffer collateral-CA1 synapses. Moreover, KIBRA knockout mice have severe deficits in contextual fear learning and memory. These results indicate that KIBRA regulates higher brain function by regulating AMPAR trafficking and synaptic plasticity.
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Project description:The single nucleotide polymorphism rs17070145 within the KIBRA gene (kidney and brain expressed protein) has been associated with variations in memory functions and related brain areas. However, previous studies yielded conflicting results, which might be due to divergent sample characteristics or task-specific effects. Therefore, we aimed to determine the impact of KIBRA genotype on learning and memory formation, and volume, microstructural integrity and functional connectivity (FC) of the hippocampus and its subfields in a well-characterized cohort of healthy older adults. One-hundred and forty subjects (72 women, age 50-80) were KIBRA genotyped and memory was tested using the Auditory Verbal Learning Task. Also, subjects underwent structural and resting-state functional magnetic resonance imaging at 3T. Subfields were delineated using automated segmentation (FreeSurfer software). Microstructural integrity was measured using mean diffusivity (MD) derived from diffusion tensor images. Seed-based analyses were used to assess FC patterns of the hippocampus. KIBRA T-allele carriers showed a trend for better memory performance, and in the hippocampus significantly higher volumes and partly lower MD, indicative for better microstructure, compared with non-T-allele carriers in the cornu ammonis (CA)2/3 and CA4/dentate gyrus subfields (all P⩽0.008, Bonferroni corrected). Also, T-allele carriers exhibited lower FC of the left hippocampus with areas outside the synchronized HC network. In sum, we could show for the first time that older T-allele carriers exhibited larger volumes and better microstructure within those hippocampus subfields that are implicated in long-term potentiation and neurogenesis, key features of memory processes. Moreover, T-allele carriers showed a more selective FC network of the hippocampus.
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