8th March 2007

Molecular mechanism of learning

SAP102 protein

Staining for the SAP102 protein (brown) in nerve cells of the mouse hippocampus. Bar represents 0.05mm

Researchers have discovered a genetic basis for higher mental functions that provides new insights into autism and learning disability. They have also uncovered ways to reverse the effects of the gene mutation using both behavioural and pharmacological approaches, opening up potential therapies for learning and cognitive disabilities.

The study, published online today in the Journal of Neuroscience and carried out by the Genes to Cognition Consortium, is the first to look at mice that lack the SAP102 gene. Male humans lacking the SAP102 gene have mental retardation or learning disabilities, including poor reading.

In the first part of the study, mice in which this gene was inactive were tested in learning tasks. The investigators found that the mice lacking the SAP102 gene do poorly on learning tasks designed to test their ability to learn spatial information, whereas mice with an active SAP102 gene improve with repeated tests.

The difference lay in their choice of strategy used to solve the task. The mice lacking the SAP102 gene used an inefficient learning strategy and therefore did not perform as well as normal mice in the learning experiment. When the SAP102 mutant mice were given extra training they could eventually perform the spatial learning task in the same time as normal mice.

The finding that improvement could be elicited by repeated training suggests that the mice benefit from 'extra lessons'. The genetic change could be overcome, at least in part, through practice. However, these over-trained SAP102 mice were still using an inefficient strategy and it took them more work to solve the task.

" This study is the latest piece in a molecular jigsaw puzzle where we are assembling the molecular components of nerve cells that underlie learning and related disease processes "

Prof Seth Grant

When the mice were tested in a different kind of learning task, which does not require spatial skills, the surprise was that the SAP102 mutant mice were quicker than normal animals. Again, the mutant mice and normal mice used different strategies, but in this learning task the strategy used by the mutants gave above-normal levels of performance.

"These studies not only help explain why humans with this mutation have learning disability, but also gives us the first clue that higher mental functions such as strategy choice are influenced by genes," commented Professor Seth Grant, who led the project.

The behavioural changes seen in the mice is similar to that seen in children with autism or Asperger's syndrome, who often do startlingly well on some psychological tests because they are able to use mental strategies that other people cannot. The team have proposed a biochemical foundation for this observation, because the SAP102 protein binds to several proteins that have mutations in autism.

In the second part of the study, the team examined the detailed biochemical and electrical changes that were altered in the nerve cells in the brain region known as the hippocampus. This brain region is important in learning in humans and mice.

The biochemical studies found that an enzyme known as ERK2 was over active in the SAP102 mutant mice. The electrical studies showed that the nerve cells in the mutant mice did not process signals in the same way as normal nerve cells do. Normal nerve cells 'learn' to respond to one another - a process called long-term potentiation (LTP) - that reinforces signals between the nerve cells. The mutant mice showed too much LTP and this could be reversed by drugs that reduce ERK2 activity.

Professor TW Robbins, Professor of Cognitive Neuroscience, University of Cambridge, commented: "This new study provides perhaps the most detailed and rigorously examined link between a form of human mental retardation caused by genetic factors to specific molecular changes in brain nerve cells. It combines studies on modified mice with comprehensive analyses of the effects of the mutation on the SAP102 protein itself, the nerve cells affected and the consequences for learning and memory."

"This sophisticated approach will be necessary for future research seeking links between molecular changes in the brain resulting from genetic factors and specific aspects of cognitive function that can be realistically related to human developmental disorders such as mental retardation and autism."

This research is a clear example of how researchers can combine genetics with neurobiology, biochemistry, mouse models and human patient research to advance our understanding of human disease and show a path toward therapeutics. The Genes to Cognition consortium brings together a team of experts in many different techniques and has shown that the team approach allows rapid progress from discovery of a human gene mutation to a detailed understanding of the biology and steps toward discovery of new therapies.

"Our wider effort is to understand the molecular basis of higher mental functions and diseases of the brain" continued Professor Grant. "We are developing a molecular model of the machinery in nerves that does this: a developing theme is that there are sets of proteins bound together into molecular machines at the junctions between nerve cells, and these machines process information. When these molecular machines are broken - as a result of gene mutations such as that of SAP102 - information is not processed properly and humans show mental disorders."

"This study is the latest piece in a molecular jigsaw puzzle where we are assembling the molecular components of nerve cells that underlie learning and related disease processes including pain, drug addiction and brain damage.""

Notes to Editors

Publication details

  • Synapse-associated protein 102/dlgh3 couples the NMDA receptor to specific plasticity pathways and learning strategies.

    Cuthbert PC, Stanford LE, Coba MP, Ainge JA, Fink AE, Opazo P, Delgado JY, Komiyama NH, O'Dell TJ and Grant SG

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2007;27;10;2673-82

Participating Centres

  • Wellcome Trust Sanger Institute, Cambridge, UK
  • Centre for Neuroscience Research, Edinburgh University, UK
  • UCLA Brain Research Institute, Los Angeles, USA


Genes to Cognition

The aim of the Genes to Cognition programme (G2C) is to establish a framework for studying genes, the brain and behaviour, and to link basic molecular research from genomes and experimental genetic organisms with human clinical studies of cognition. G2C is a multidisciplinary consortium of researchers. It is primarily based at the Wellcome Trust Sanger Institute, and is directed by Professor Seth Grant. G2C is international, with members and collaborators worldwide.

The Wellcome Trust Sanger Institute

The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms and more than 90 pathogen genomes. In October 2006, new funding was awarded by the Wellcome Trust to exploit the wealth of genome data now available to answer important questions about health and disease.


The Wellcome Trust

The Wellcome Trust is the largest charity in the UK. It funds innovative biomedical research, in the UK and internationally, spending around £500 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing.


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