Barrett laboratory: Neural plasticity and neurotrophins
On his return to Australia in 1992, Graham decided to apply his molecular biological skills to the study of the nervous system, and joined the laboratory of Perry Bartlett at the Walter and Eliza Hall Institute of Medical Research. In 1993 he discovered that the p75 nerve growth factor (NGF) receptor initiated apoptosis when not bound to NGF. This was published in the Proceedings of the National Academy of Sciences of the USA in 1994, and has become seen as a breakthrough paper and a Neuroscience citation classic. It meant that neurons that express p75 were dependent on NGF for survival. This meant that p75 could signal without a ligand, a concept that was unknown and not accepted by the scientific community at that time. Now, p75's apoptotic role is accepted by all, and p75 is also considered by many to be the prototype of the dependence receptor family… a family of some 20 structurally dissimilar receptors, all of which cause apoptosis if their supply of ligand is cut off.
Graham rejoined the Physiology Department in 1995. Whilst continuing to work on the p75 NGF receptor (now renamed as the p75 neurotrophin receptor), he has increasingly focused on its effects on memory and Alzheimer's Disease. He has shown that reducing p75 expression improves the memory of normal mice. Reducing p75 in "Mouse-zeimer's disease" (yes, mice can contract Alzheimer 's disease too) restores these mice to normal function in all memory tests so far tried. Thus the p75 neurotrophin receptor is an exciting new target for developing drugs to treat AD.
Neurotrophins and their receptors, including p75, are at the very core of neural plasticity that underlies memory, cognition and behavior. Increasingly, computational and mathematical tools are being used to better understand the neural networks underlying these phenomena, and the shaping of these networks by neurotrophins. Dr Barrett is currently applying these tools to his own research.
An exciting new field, poised to cause a major shift in our understanding of the brain, is the nexus between neurotrophins (and the p75 neurotrophin receptor) and depression. The emergence of NMDA antagonists in depression treatment is a particularly interesting example of this, as they work (in part) by stimulating neurotrophins and resetting neural networks governing mood and behavior. Dr Barrett is involved at the forefront of clinical and laboratory research in this exciting new field.
Throughout his research career, Dr Barrett has continued to work as an active and busy clinician. At an early stage of his career he developed an interest in the debilitating, and sometimes tragic, disease of depression. In 2001 and 2002 he undertook advanced training in the treatment of depression and anxiety. He has participated in numerous clinical colloquia about depression treatment, and has amassed almost 30 years of experience in treating this disease.
Current Research Projects
- Neurotrophins, Neural Networks and Depression
- p75 and the Septo-Hippocampal Memory System
- p75 and Alzheimer's Disease
- Computer simulation of the Septo-Hippocampal system
- Using peptide carriers to transport antisense and siRNA molecules across the blood-brain barrier
The Barrett lab's research utilizes genetically identical (except for the gene of interest) mice that have been developed over a decade of breeding and back-crossing;
Control strain 129 Sv/ter: –a "wild-type" mouse that carries the standard two normal copies of the p75 gene per diploid cell. This strain is inbred to the extent that the mice are homozygous at every locus, and every mouse is genetically identical.
p75 +/- (heterozygous) mice: - they have only one functional p75 gene per cell, and are otherwise identical to the control strain.
p75 -/- (knockout) mice:- zero copies of the functional p75 gene per cell. Otherwise genetically identical to the control strain.
Tg2576: - transgenic mice carrying the "Swedish mutation" of the human APP gene. This two amino acid mutation causes an increased proportion of APP to be broken down into the highly toxic Aβ(1-42) form of amyloid peptide. This gene is responsible for a rare familial form of Alzheimer's Disease in humans. The mice have increased levels of amyloid peptide in the brain and eventually develop amyloid plaques (but not neurofibrillary tangles). They have memory and cognitive impairment that roughly parallels the increase in amyloid peptide in the brain. They have been back-crossed with the 129 Sv/ter strain so that they share the same genetic background.
Tg2576/p75+/-: - Tg2576 mice that carry only one functional p75 gene per cell. They have been shown by us to produce half of the normal amount of p75. They too have been back-crossed with the 129 Sv/ter strain.
Tg2576/p75-/-: - Tg2576 mice that have no functional p75, i.e., p75 is knocked out. Genetic background is identical to other strains in our colony; all of our lab's experimental mice share exactly the same genetic background.
- Murphy M, Wilson YM, Vargas E, Munro KM, Smith B, Huang A, Li QX, Xiao J, Masters CL, Reid CA, Barrett GL (2014). p75 reduction ameliorates the cognitive deficits in a model of Alzheimer's disease. Neurobiology of Aging (In Press). Impact Factor = 5.1
- Greferath U, Trieu J, Barrett GL. The P75 Neurotrophin Receptor Has Nonapoptotic Antineurotrophic Actions In The Basal Forebrain. J Neuroscience Research 2012; 90: 278-87.
- Khaziev EF, Fatikhov NF, Samigullin DV, Barrett GL, Bukharaeva EA, Nikolsky EE. Decreased entry of calcium into motor nerve endings upon activation of presynaptic cholinergic receptors. Dokl Biol Science (Proceedings of the Russian Academy of Science, Biology Section) 2012; 446: 283-5.
- Barrett GL, Reid CA, Tsafoulis C, Zhu W, Williams DA, Paolini AG, Murphy M and Trieu J. Enhanced Spatial Memory and Hippocampal Long Term Potentiation in p75 Neurotrophin Receptor Knockout Mice. Hippocampus 2010; 20: 145-52.
- Xiao J, Wong AW, Willingham MM, Kaasinen SK, Hendry IA, Barrett GL, Kilpatrick TK and Murray SS. BDNF exerts contrasting effects on peripheral myelination of NGF-dependent and BDNF-dependent DRG neurons. Journal of Neuroscience 2009; 29: 4016-4022.
- Barrett GL, Trieu J and Naim T. The Identification of Leptin-Derived Peptides that are Taken up by the Brain. Regulatory Peptides 2009; 155: 55-61.
- Barrett GL, Bennie A, Trieu J, Ping SE and Tsafoulis C. The chronology of age-related spatial learning impairment in two rat strains, as tested by the Barnes maze. Behavioral Neuroscience 2009; 123: 533-538.
- Ping SE, Trieu J, Wlodek ME, Barrett GL. Effects of estrogen on basal forebrain cholinergic neurons and spatial learning. Journal of Neuroscience Research 2008; 86(7): 1588-98.
- Epa WR, Markovska K, Barrett GL. The p75 Neurotrophin Receptor Enhances TrkA Signaling by Binding to Shc and Enhancing its Phosphorylation. Journal of Neurochemistry 2004; 89: 344-53.
- Greferath U, Bennie AM, Kourakis A, Bartlett PF, Murphy M, Barrett GL. Enlarged Cholinergic Forebrain Neurons And Improved Spatial Learning In P75 Knockout Mice. European Journal of Neuroscience 2000; 12: 885-893.
- Barrett GL, Bartlett PF. The p75 NGF Receptor Mediates Survival or Death Depending on the Stage of Sensory Neurone Development. Proc Natl Acad Sci USA 1994; 91: 6501-6505.
This Research Group doesn't currently have any projects
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For further information about this research, please contact Associate Professor Graham Barrett