Scientists at The Hospital for Sick Children (SickKids) have discovered key molecular steps in the way a single protein disrupts the connections between brain cells (neurons). The study is published in the August 12 advance online edition of Nature Neuroscience.
It is thought that increasing the connectivity between neurons is important for memory formation. Previous research found that the protein myocyte enhancer factor 2 (MEF2) disrupts the connections between neurons growing in a dish. This latest study, led by Dr. Sheena Josselyn, principal investigator of the study and Senior Scientist in the Neurosciences & Mental Health Program at SickKids, examined the effects of increasing or decreasing the levels of MEF2 on memory formation using an animal model.
The research team found that increasing MEF2 blocked memory formation while decreasing levels of the protein enhanced it, meaning the animal remembered things it normally would not.
MEF2 and many of its more downstream partners have been implicated in several human cognitive or psychiatric disorders, including Autism Spectrum Disorder (ASD), Angelman syndrome and a Rett-like syndrome.
“These findings suggest that the cognitive deficits in these human disorders may be caused by a disruption of the MEF2-mediated gene network that regulates structural plasticity and memory formation,” says Josselyn, who is also Associate Professor in the Department of Physiology at the University of Toronto.
Dr. Paul Frankland, another investigator involved in the study and Senior Scientist at SickKids noted that “because we observed severe memory deficits when we acutely decreased MEF2 function in the adult brain, this brings up the possibility that these human cognitive disorders may not result solely from untreatable developmental abnormalities but might be due to chronic dysregulation of the MEF2 function that is necessary for normal memory formation.”
The study went on to examine how MEF2 blocked memory formation and found that the memory-disruptive effects of this protein could be rescued by interfering the movement of AMPA receptors, which are normally located in the area where neurons make connections.
Josselyn explains that if these AMPA receptors are located on the surface of a cell, they enable fast neurotransmission, or talking between connected cells. However, if these AMPA receptors are pulled into the interior of the cell, they cannot mediate this ‘fast talk’.
The study showed that the memory deficits produced by MEF2 were reversed by interfering with the “pulling in” of AMPA receptors, which Josselyn explains, could mean that impaired movement or trafficking of AMPA receptors (with excessive “pulling in”) may contribute to the cognitive dysfunction observed in several human disorders and may be a potential therapeutic target.
This study was supported by the Canadian Institutes of Health Research, the EJLB Foundation, Natural Science and Engineering Research Council,Restracomp Fellowshipsat SickKids, , the Alzheimer’s Society of Canada, CIHR Frederick Banting and Charles Best Canada Graduate Scholarships Doctoral Award, the Faculty of Medicine at the University of Toronto, an Ontario Graduate Scholarship and SickKids Foundation.
The Hospital for Sick Children (SickKids)