BDNF Val66Met Genotype Interacts With a History of Simulated Stress Exposure to Regulate Sensorimotor Gating and Startle Reactivity.
Reduced expression of Brain-Derived Neurotrophic Factor (BDNF) has been implicated in the pathophysiology of schizophrenia. The BDNF Val66Met polymorphism, which results in deficient activity-dependent secretion of BDNF, is associated with clinical features of schizophrenia. We investigated the effect of this polymorphism on Prepulse Inhibition (PPI), a translational model of sensorimotor gating which is disrupted in schizophrenia. We utilized humanized BDNFVal66Met (hBDNFVal66Met) mice which have been modified to carry the Val66Met polymorphism, as well as express humanized BDNF in vivo. We also studied the long-term effect of chronic corticosterone (CORT) exposure in these animals as a model of history of stress. PPI was assessed at 30ms and 100ms interstimulus intervals (ISI). Analysis of PPI at the commonly used 100ms ISI identified that, irrespective of CORT treatment, the hBDNFVal/Met genotype was associated with significantly reduced PPI. In contrast, PPI was not different between hBDNFMet/Met and hBDNFVal/Val genotype mice. At the 30ms ISI, CORT treatment selectively disrupted sensorimotor gating of hBDNFVal/Met heterozygote mice but not hBDNFVal/Val or hBDNFMet/Met mice. Analysis of startle reactivity revealed that chronic CORT reduced startle reactivity of hBDNFVal/Val male mice by 51%. However, this was independent of the effect of CORT on PPI. In summary, we provide evidence of a distinct BDNFVal66Met heterozygote-specific phenotype using the sensorimotor gating endophenotype of schizophrenia. These data have important implications for clinical studies where, if possible, the BDNFVal/Met heterozygote genotype should be distinguished from the BDNFMet/Met genotype.
Behavioural Neuroscience Laboratory, Florey Institute of Neuroscience and Mental Health, Melbourne, Australia.|Psychoneuroendocrinology Laboratory, Florey Institute of Neuroscience and Mental Health, Melbourne, Australia.
Michael J
MJ
Notaras
Psychoneuroendocrinology Laboratory, Florey Institute of Neuroscience and Mental Health, Melbourne, Australia.
Rachel A
RA
Hill
Departments of Biophysics and Neuroscience, Columbia University, New York, NY, USA.
Joseph A
JA
Gogos
Behavioural Neuroscience Laboratory, Florey Institute of Neuroscience and Mental Health, Melbourne, Australia.|School of Psychology and Public Health, La Trobe University, Melbourne, Australia.|The College of Public Health, Medical and Veterinary Sciences, James Cook University, Queensland, Australia.
Maarten
M
van den Buuse
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D003345:Corticosterone / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D008715:Methionine / Q000235:genetics; D008810:Mice, Inbred C57BL; D065808:Prepulse Inhibition / Q000235:genetics; D011618:Psychotic Disorders / Q000235:genetics*; D013216:Reflex, Startle / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*; D055139:Sensory Gating / Q000235:genetics*; D013256:Steroids / Q000494:pharmacology; D013315:Stress, Psychological / Q000139:chemically induced / Q000235:genetics*; D014633:Valine / Q000235:genetics
D019208:Brain-Derived Neurotrophic Factor; D013256:Steroids; C579455:BDNF protein, human; D008715:Methionine; D014633:Valine; D003345:Corticosterone
BDNF; G196A; Val66Met; brain-derived neurotrophic factor; glucocorticoid hormones; prepulse inhibition; psychosis; rs6265; schizophrenia; sensorimotor gating; stress