Feature: Genes and cognition
Animals as diverse as sea slugs, fruit flies and mice (and occasionally even humans) can learn. But how are memories stored in the brain and accessed? And how do these processes relate to human learning impairment, cognitive decline with ageing, dementias and schizophrenia?
Over the next five years, the £6 million Genes to Cognition (G2C) programme aims to answer some of these questions. Led by Professor Seth Grant, previously at the University of Edinburgh and now at the Wellcome Trust Sanger Institute, G2C brings together experts in many areas – such as computer science, genetics, neuroscience and psychiatry. “Genes to Cognition is a unique project,” asserts Professor Grant. “This is a highly integrated programme that goes from the structure of individual genes all the way to aspects of cognition, human behaviour and psychiatric disorders.”
Like a computer, the brain is fed data, in the form of nerve impulses. But while a computer will merely crunch the data, the nerve impulses arriving at the brain actually change the properties of the structures they pass through. There are subtle changes in the strength of signals transmitted through the junctions (synapses) between nerves. This phenomenon, synaptic plasticity, is a form of cellular ‘memory’.
Crucial to this process is a protein called the NMDA receptor, which sits at synapses in the central nervous system. Professor Grant and others have found additional molecules involved in synaptic plasticity. For example, mice lacking a protein called PSD-95, which binds to the NMDA receptor, have severe learning deficits. By the end of the 1990s, more than 100 such molecules had been implicated, although it was not clear how their roles fitted together.
An answer came in 2000, when Professor Grant’s team found that the NMDA receptor is associated not only with PSD-95, but also with many other proteins. At least 100 proteins appeared to function together as a large machine, translating the electrical information of nerve impulses into changes in the cell that store the information. The existence of such a mechanism was first mooted by Donald Hebb in 1949, and so Professor Grant has dubbed the complex containing the NMDA receptor and other proteins the ‘hebbosome’ in his honour.
An integrated programme
Importantly, says Professor Grant, a better understanding of the genes involved with learning is likely to be relevant clinically. As an example, he points to the discovery by Lucy Raymond of mutations in a human X chromosome gene that cause severe learning disability (see page 20). The human gene, DLG3, is a close relative of the mouse PSD95 gene. “Several years ago, we showed that PSD95 knockout mice have a severe learning impairment,” he says. “Now it’s been shown that this type of gene is equally important in humans.”
The G2C programme is multi-stranded. A first step is to select which genes to study. Many genes have been implicated in learning and behaviour and in human psychiatric disorders, and the 100 genes involved with the NMDA receptor may well have a role in cognition. But the proteins produced by these genes may interact with many other proteins, so there could be 1000 genes involved.
Another task is to examine whether variations in these genes are associated with human mental illnesses. For example, Professor Douglas Blackwood at the University of Edinburgh is searching for genes associated with schizophrenia, and Professor Ian Deary, also in Edinburgh, is looking for genetic variations and other factors associated with individual differences in age-related cognitive decline (see box).
Function will be studied in mice lacking a specific gene, or in which a gene has been modified in a specific way. “The Sanger Institute will have an important contribution for this part of the research,” says Professor Grant. “For example, if we find that certain genetic variants [SNPs] are associated with human mental illness, we can make mice with the same variant and examine its effect.”
Once the genetically modified mice have been made, the effects of the modifications will be examined in many different ways. “We need to study the function of the genes in specific nerves, to look at the expression of the genes and their proteins, their role in electrophysiology, and their involvement in forms of behaviour,” says Professor Grant. “So for this stage of the programme, G2C involves many different researchers from across the UK, each with different specialisms and expertise.”
Finding the role of genes in cognition would have huge implications for medicine, and not only for neuropsychiatric disorders. “Understanding pain and addiction, improved diagnostics and treatments for disease, all could benefit,” says Professor Grant. “Understanding the mechanisms of human behaviour is the challenge – the greatest challenge of the 21st century.”