Scientists reveal molecular sculptor of memories

Researchers working with adult mice have discovered that learning and memory were profoundly affected when they altered the amounts of a certain protein in specific parts of the mammals' brains.

The protein, called kibra, was linked in previous studies in humans to memory and protection against late-onset Alzheimer's disease. The new work in mice, reported in the Sept. 22 issue of Neuron, shows that kibra is an essential part of a complex of proteins that control the sculpting of brain circuitry, a process that encodes memory.

"There are populations of humans who are slightly smarter and have better memory recall than others, and these traits have been mapped to the gene that codes for the kibra protein" says Richard L. Huganir, Ph.D., professor and director of the Solomon H. Snyder Department of Neuroscience at the Johns Hopkins University School of Medicine, and a Howard Hughes Medical Institute investigator. "Our studies in mice show that this same gene is involved in the operation of synapses, through which neurons communicate, and in brain plasticity, suggesting that's what its role might be in humans too."

In their lab, Huganir and neuroscience graduate student Lauren Makuch isolated kibra from mouse brain cells and confirmed by standard biochemical tests that it interacted with a neurotransmitter receptor in the brain known as the AMPA receptor.

They then determined that kibra regulated the delivery of AMPA receptors from inside the brain's nerve cells out to the synapses by first growing live brain cells from embryonic mice in a dish for two weeks and then genetically altering some of those cells to produce less kibra protein. Next, they placed the live neurons in an imaging chamber and recorded the activity of the AMPA receptors once a minute for 60 minutes. Results showed that AMPA receptors moved faster in the cells with less kibra than in control cells with normal amounts of the protein demonstrating that kibra regulates how receptors are delivered to the surface of brain cells.

The work affirms that the addition of AMPA receptors to synapses serves to strengthen connections in the brain, Huganir says, noting that most forms of learning involve the strengthening of some synapses and the weakening of others, a phenomenon known as plasticity, which is responsible for sculpting circuits in the brain that encode memory. Without kibra, this process doesn't function properly; as a result, learning and memory are compromised. Huganir hypothesizes that kibra specifically helps create a pool of receptors that is used to add receptors to synapses during learning.

Later in their study, using slices of brain from mice with or without kibra, postdoctoral fellow Lenora Volk recorded and measured electrical activity and synaptic plasticity in nerve cells, noting that mice lacking kibra showed less plasticity, a phenomenon that translates into a reduced ability to learn and recall new information, Makuch explains.

Finally, the Hopkins researchers conducted a series of behavioral studies using adult mice to compare the learning and memory of normal mice with those that made much less kibra protein. They used a well-established fear-conditioning task by placing the mice in a training chamber and exposing them to a tone and subsequent shock. After two days of training, the animals' rates of "freezing" in place -- a normal rodent response to fear -- were measured. Kibra-deficient mice took longer to learn to associate the tone with the shock than it did the others. On day three of the experiment, upon simply being placed back into the training chamber, the normal mice had a high rate of freezing, while the kibra-deficient mice had a very low rate, indicating impairments in contextual fear response and therefore, memory.

"Our work in the mammalian brain shows that kibra, required for normal brain function and associated with learning and memory, is important for regulating the trafficking of AMPA receptors," Huganir says. "In addition, as kibra has been associated with protection against early onset Alzheimer's disease, these studies may help define novel therapeutic targets for the treatment of age-related memory disorders."

This study was funded by the National Institutes of Health and the Howard Hughes Medical Institute.

Authors on the paper, in addition to Huganir, Makuch and Volk are Victor Anggono, Richard C. Johnson, and Yilin Yu, all of Johns Hopkins.

Other authors are Kerstin Duning and Joachim Kremerskothen, University Hospital Münster, Germany; Jun Xia, The Hong Kong University of Science and Technology, China; and Kogo Takamiya, University of Miyazaki, Japan.

Scientists and engineers create the 'perfect plastic'

Researchers at the University of Leeds and Durham University have solved a long-standing problem that could revolutionize the way new plastics are developed. The breakthrough will allow experts to create the 'perfect plastic' with specific uses and properties by using a high-tech 'recipe book.' It will also increase our ability to recycle plastics. The research paper is published in the journal Science on September 29.

The paper's authors form part of the Microscale Polymer Processing project, a collaboration between academics and industry experts which has spent 10 years exploring how to better build giant 'macromolecules.' These long tangled molecules are the basic components of plastics and dictate their properties during the melting, flowing and forming processes in plastics production.

Low-density polyethylenes (LDPEs) are used in trays and containers, lightweight car parts, recyclable packaging and electrical goods. Up until now, industry developed a plastic then found a use for it, or tried hundreds of different "recipes" to see which worked. This method could save the manufacturing industry time, energy and money.

The mathematical models used put together two pieces of computer code. The first predicts how polymers will flow based on the connections between the string-like molecules they are made from. A second piece of code predicts the shapes that these molecules will take when they are created at a chemical level. These models were enhanced by experiments on carefully synthesised 'perfect polymers' created in labs of the Microscale Polymer Processing project.

Dr. Daniel Read, from the School of Mathematics, University of Leeds, who led the research, said, "Plastics are used by everybody, every day, but until now their production has been effectively guesswork. This breakthrough means that new plastics can be created more efficiently and with a specific use in mind, with benefits to industry and the environment."

Professor Tom McLeish, formerly of the University of Leeds, now Pro-Vice Chancellor for Research at Durham University leads the Microscale Polymer Processing project. He said, "After years of trying different chemical recipes and finding only a very few provide useable products, this new science provides industry with a toolkit to bring new materials to market faster and more efficiently."

Professor McLeish added that as plastics production moves from oil-based materials to sustainable and renewable materials, the "trial and error" phase in developing new plastics could now be by-passed. He said, "By changing two or three numbers in the computer code, we can adapt all the predictions for new bio-polymer sources."

"This is a wonderful outcome of years of work by this extraordinary team. It's a testimony to the strong collaborative ethos of the UK research groups and global companies involved," he added.

Dr. Ian Robinson of Lucite International, one of the industrial participants in the wider project said, "The insights offered by this approach are comparable to cracking a plastics 'DNA.'"

The model was developed by Dr. Daniel Read, School of Mathematics, University of Leeds, Dr. Chinmay Das of the School of Physics & Astronomy, University of Leeds and Professor Tom McLeish, Department of Physics, Durham University. Their predictions were compared to the results of polymer analysis by Dr. Dietmar Auhl, at the time a physicist at Leeds.

The research was carried out at the University of Leeds, Durham University, LyondellBasell and Dow Chemical and was funded by the Engineering and Physical Sciences Research Council and the European Union.

The Microscale Polymer Processing collaboration includes researchers from the universities of Durham, Bradford, Cambridge, Leeds, Nottingham, Oxford, Reading, Sheffield and University College London alongside their industry counterparts from Lucite International, Ineos, LyondellBasell, BASF, Dow Chemical, DSM, and Mitsubishi.