Defining the genetic basis for individual differences in learning

Funding Round: 1 2013-2015

Research Question: Determine how the protein Kibra confers better memory to some people.

Interdisciplinary Approach: This project combines human genetic-behavior studies with molecular, cellular and physiological studies in a variety of laboratory models including neuronal cell culture and genetically modified mice.

Potential Implications of Research: These studies help to identify new pathways in the regulation of learning and memory, and may provide novel therapeutic targets for the treatment of human memory disorders.

Project Description: Memory performance is an integral part of human intelligence. Genome-wide screening studies have suggested a strong association between a single nucleotide polymorphism (SNP) in the KIBRA gene and human memory performance. People carrying this SNP have significantly better memory compared to non-carriers. The KIBRA gene encodes a protein that is expressed at high levels in brain and kidney. Understanding the mechanism by which the KIBRA SNP affects Kibra protein function and improves human memory can help us device a clinical strategy to improve human intelligence, and help patients suffering from memory loss due to diseases such as Alzheimer’s disease.

Synapses are the sites of communication between neurons. At synapses, neurotransmitters are released to bind to receptors.  AMPA receptors are the major excitatory neurotransmitter receptors in the brain. At the molecular level, AMPA receptor trafficking into and from synapses is one of the mechanisms underlying learning and memory. Previous studies in our lab have found that Kibra is a key molecule regulating AMPA receptor trafficking, as well as synaptic plasticity, and learning and memory in mice. However, the actual mechanism is still unknown.

In this project, we used cognitive and imaging approaches to further investigate the genetic association of KIBRA variants with human memory, and explored the molecular and cellular mechanisms underlying Kibra’s effect on memory in mouse model systems. We found Kibra binds to AMPA receptor trafficking complex, and regulates AMPA receptor trafficking through endosomal vesicles in neurons. We have identified two SNPs in Kibra’s C2 domain that co-segregate with the SNP that is associated with human memory performance. These SNPs altered the phosphor-lipid binding pattern of C2 domain, and recently we found the presence of these SNPs decreases Kibra binding to each other. We confirmed that these novel Kibra SNPs have the same differential association between hippocampal formation activity and increased age. These SNPs provide important tools to explore the molecular mechanisms underlying individual intelligence differences in human.

These studies demonstrated that Kibra is a member of AMPA receptor trafficking complex. It may directly regulate AMPA receptor membrane trafficking during neural activity; and the C2-domain mediated protein-protein interactions between two Kibra molecules or between Kibra and other proteins may play a role in such regulation. These studies improved our understanding of the molecular basis underlying the individual differences in human memory performance caused by KIBRA genetic variants, helped identify new pathways in the regulation of learning and memory, and may provide novel therapeutic targets for the treatment of human memory disorders.