Cognitive-Behavioural Effects of Chronic Adolescent Stress in Val66Met Polymorphism Knock-In Mice Carrying a Humanised Copy of the Brain-Derived Neurotrophic Factor (hBDNF) Gene: Implications for Neuropsychiatric Disorders & Cognitive Dysfunction
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1
Florey Institute of Neuroscience & Mental Health, Australia
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2
University of Melbourne, Florey Department of Neuroscience & Mental Health, Australia
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3
Columbia University, Department of Cellular Biophysics & Department of Neuroscience, United States
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4
University of Melbourne, Department of Pharmacology, Australia
Background
Brain-derived neurotrophic factor (BDNF) is the most abundantly expressed neurotrophin within the mammalian brain. The Val66Met functional single nucleotide polymorphism in the BDNF gene produces an amino acid residue substitution from valine (Val) to methionine (Met) at codon 66 in the 5’ pro-region of BDNF. The BDNF Val66Met polymorphism results in the aberrant packaging and release of mature BDNF, and has been associated with morphological abnormalities of the hippocampal formation, deficits in cognitive function and has been linked to a number of psychiatric disorders. Here we present the preliminary results of a phenotyping exercise for a BDNF Val66Met polymorphism knock-in mouse that expresses human BDNF in place of the mouse equivalent.
Methods
Transgenic mice carrying a wildtype (Val/Val) or mutant (Val/Met; Met/Met) hBDNF genotype were weaned at four weeks of age and were subsequently group-housed in individually ventilated cages. A chronic adolescent stress treatment (25mg/L of corticosterone) was administered to mice between six to eight weeks of age, followed by a two-week washout period. Following from this, Y-maze, light-dark box, fear conditioning, prepulse inhibition and forced swim test performance was examined.
Results
Preliminary results suggest that the genetic depletion of BDNF through the activity-dependent pathway produced deficits in hippocampal- and amygdala-dependent memory, and that the chronic adolescent stress treatment tended to improve memory performance, in 66Met allele-carriers. Consistent with previous research, preliminary analysis also suggests that male Met/Met homozygote mice are more anxious than the other genotype groups.
Discussion
Preliminary results are consistent with previous animal model work, and supports human studies that have sampled both disordered and healthy Val66Met carriers. Contrary to expectations, the chronic adolescent stress treatment tended to improve memory performance in the 66Met allele-carriers. This result may provide insight into why some population studies have reported that the mutant 66Met allele is protective, as opposed to risk conferring, for some neuropsychiatric disorders such as schizophrenia. With further molecular analysis, this mouse model may lead to the identification of novel therapeutic targets that could be exploited to better treat the cognitive symptoms reported across a number of psychiatric illnesses associated with the Val66Met polymorphism.
Keywords:
Brain-Derived Neurotrophic Factor,
val66met,
Val66Met Polymorphism,
Memory,
stress,
Schizophrenia,
Depression,
Anxiety,
BDNF,
hBDNF,
Animal Models,
Translational Neuroscience,
translational psychiatry,
cognitive dysfunction,
Val66Met Mice,
66Val,
66Met
Conference:
ACNS-2013 Australasian Cognitive Neuroscience Society Conference, Clayton, Melbourne, Australia, 28 Nov - 1 Dec, 2013.
Presentation Type:
Poster
Topic:
Memory
Citation:
Notaras
MJ,
Gogos
J and
Van Den Buuse
M
(2013). Cognitive-Behavioural Effects of Chronic Adolescent Stress in Val66Met Polymorphism Knock-In Mice Carrying a Humanised Copy of the Brain-Derived Neurotrophic Factor (hBDNF) Gene: Implications for Neuropsychiatric Disorders & Cognitive Dysfunction.
Conference Abstract:
ACNS-2013 Australasian Cognitive Neuroscience Society Conference.
doi: 10.3389/conf.fnhum.2013.212.00063
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Received:
15 Oct 2013;
Published Online:
25 Nov 2013.
*
Correspondence:
Mr. Michael J Notaras, Florey Institute of Neuroscience & Mental Health, Melbourne, Australia, mnotaras@student.unimelb.edu.au