The BDNF Val66Met polymorphism (rs6265) enhances dopamine neuron graft efficacy and side-effect liability in rs6265 knock-in rats

Mercado, Natosha M.; Stancati, Jennifer A.; Sortwell, Caryl E.; Mueller, Rebecca L; Boezwinkle, Samuel A.; Duffy, Megan F.; Fischer, D. Luke; Sandoval, Ivette M.; Manfredsson, Fredric P.; Collier, Timothy J.; Steece‐Collier, Kathy

doi:10.1016/j.nbd.2020.105175

Cited by 15 publications

(60 citation statements)

References 139 publications

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“…ELISA showed no differences between the genotypes in the levels of BDNF in the ventral hippocampus when sexes were combined, although a small decrease was observed in Val/Met females. We previously observed a similar result of no change in BDNF protein levels in the dorsal hippocampus, ventral hippocampus, and medial prefrontal cortex of Val66Met mice [ 20 ], in line with a previous study reporting that BDNF release, not BDNF levels, were reduced in rats with the Met/Met genotype [ 34 ]. There were also no significant differences between genotypes in full-length, truncated, or phosphorylated TrkB expression in Val66Met mice [ 20 ] but further studies are required to verify if this is similarly the case in our Val68Met rat model.…”

Section: Discussionsupporting

confidence: 86%

“…Male and female outbred rs6265 (Val68Met) rats with the Met/Met genotype were originally obtained from Dr Caryl Sortwell (Michigan State University, MI, USA) and a breeding colony was established at the Australian Resource Center (ARC, WA, Australia). Full details of the generation of this rat model have been published [ 34 ]. Briefly, these rats carry the valine to methionine polymorphism (Val68Met) in the rat Bdnf gene (GenBank: NM_001270630; Ensembl: ENSRNOG00000047466).…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, these rats carry the valine to methionine polymorphism (Val68Met) in the rat Bdnf gene (GenBank: NM_001270630; Ensembl: ENSRNOG00000047466). This Bdnf knock-in rat model was generated in Sprague-Dawley rats by Cyagen Biosciences (Santa Clara, CA, USA) using CRISPR/Cas-mediated homologous recombination [ 34 ]. For the present study, Met/Met founder rats at ARC were mated with Sprague-Dawley controls to generate heterozygous Val/Met rats.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, a rat model of the Val66Met polymorphism has been developed carrying a valine to methionine substitution (Val68Met) in the rat Bdnf gene [ 34 ]. While all previous animal models of the Val66Met polymorphism have been in mice due to the ability to more easily genetically modify the mouse genome previously, rats have been the animal model of choice for behavioral neuroscience research for over a century [ 35 , 36 ].…”

Section: Introductionmentioning

confidence: 99%

“…Because rats have two additional threonine amino acids at positions 57 and 58, this rat Val68Met is equivalent to the human Val66Met SNP. In vitro BDNF release was confirmed to be reduced from cultured neurons from Met/Met rats without altering total BDNF brain tissue content [ 34 ]. The current study investigates the baseline behavioral phenotype of these Val68Met rats over a range of anxiety and memory tasks, with a particular focus on fear behavior which BDNF Val66Met has been implicated in [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

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Behavioral phenotyping of a rat model of the BDNF Val66Met polymorphism reveals selective impairment of fear memory

et al. 2022

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The common brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with reduced activity-dependent BDNF release and increased risk for anxiety disorders and PTSD. Here we behaviorally phenotyped a novel Val66Met rat model with an equivalent valine to methionine substitution in the rat Bdnf gene (Val68Met). In a three-day fear conditioning protocol of fear learning and extinction, adult rats with the Met/Met genotype demonstrated impaired fear memory compared to Val/Met rats and Val/Val controls, with no genotype differences in fear learning or extinction. This deficit in fear memory occurred irrespective of the sex of the animals and was not seen in adolescence (4 weeks of age). There were no changes in open-field locomotor activity or anxiety measured in the elevated plus maze (EPM) nor in other types of memory measured using the novel-object recognition test or Y-maze. BDNF exon VI expression in the dorsal hippocampus was higher and BDNF protein level in the ventral hippocampus was lower in female Val/Met rats than female Val/Val rats, with no other genotype differences, including in total BDNF, BDNF long, or BDNF IV mRNA. These data suggest a specific role for the BDNF Met/Met genotype in fear memory in rats. Further studies are required to investigate gene–environment interactions in this novel animal model.

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Section: Discussionsupporting

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Behavioral phenotyping of a rat model of the BDNF Val66Met polymorphism reveals selective impairment of fear memory

et al. 2022

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Chronic running‐wheel exercise from adolescence leads to increased anxiety and depression‐like phenotypes in adulthood in rats: Effects on stress markers and interaction with BDNF Val66Met genotype

Jaehne

Kent

Lam

et al. 2022

Developmental Psychobiology

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Exercise has been shown to be beneficial in reducing symptoms of affective disorders and to increase the expression of brain-derived neurotrophic factor (BDNF). The BDNF Val66Met polymorphism is associated with reduced activity-dependent BDNF release and increased risk for anxiety and depression. Male and female Val66Met rats were given access to running wheels from 3 weeks of age and compared to sedentary controls. Anxiety-and depression-like behaviors were measured in adulthood using the elevated plus maze (EPM), open field (OF), and forced swim test (FST). Expression of BDNF and a number of stress-related genes, the glucocorticoid receptor (Nr3c1), serum/glucocorticoid-regulated kinase 1 (Sgk1), and FK506 binding protein 51 (Fkbp5) in the hippocampus were also measured. Rats given access to running wheels developed high levels of voluntary exercise, decreased open-arm time on the EPM and center-field time in the OF, reduced overall exploratory activity in the open field, and increased immobility time in the FST with no differences between genotypes. Chronic exercise induced a significant increase in Bdnf mRNA and BDNF protein levels in the hippocampus with some of these effects being genotype specific. Exercise decreased the expression of Nr3c1 and Sgk1, but increased the expression of Fkbp5. These results suggest that chronic running-wheel exercise from adolescence increased anxiety and depression-like phenotypes in adulthood, independent of BDNF Val66Met genotype.Further studies are required to confirm that increased indices of anxiety-like behavior are independent from reduced overall locomotor activity.

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Enhanced methamphetamine sensitisation in a rat model of the brain-derived neurotrophic factor Val66Met variant: Sex differences and dopamine receptor gene expression

Jaehne,

Semaan,

Grosman

et al. 2023

Neuropharmacology

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The BDNF Val66Met polymorphism (rs6265) enhances dopamine neuron graft efficacy and side-effect liability in rs6265 knock-in rats

Cited by 15 publications

References 139 publications

Behavioral phenotyping of a rat model of the BDNF Val66Met polymorphism reveals selective impairment of fear memory

Behavioral phenotyping of a rat model of the BDNF Val66Met polymorphism reveals selective impairment of fear memory

Chronic running‐wheel exercise from adolescence leads to increased anxiety and depression‐like phenotypes in adulthood in rats: Effects on stress markers and interaction with BDNF Val66Met genotype

Enhanced methamphetamine sensitisation in a rat model of the brain-derived neurotrophic factor Val66Met variant: Sex differences and dopamine receptor gene expression

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