Working Memory Deficits, Increased Anxiety-like Traits, and Seizure Susceptibility in BDNF Overexpressing Mice

Overview

Journal Learn Mem

Specialty Neurology

Date 2011 Jul 28

PMID 21791566

Citations 52

Authors

Francesco Papaleo

Jill L Silverman

Jordan Aney

Qingjun Tian

Charlotte L Barkan

Kathryn K Chadman

Jacqueline N Crawley

Affiliations

Soon will be listed here.

Abstract

BDNF regulates components of cognitive processes and has been implicated in psychiatric disorders. Here we report that genetic overexpression of the BDNF mature isoform (BDNF-tg) in female mice impaired working memory functions while sparing components of fear conditioning. BDNF-tg mice also displayed reduced breeding efficiency, higher anxiety-like scores, high self-grooming, impaired prepulse inhibition, and higher susceptibility to seizures when placed in a new empty cage, as compared with wild-type (WT) littermate controls. Control measures of general health, locomotor activity, motor coordination, depression-related behaviors, and sociability did not differ between genotypes. The present findings, indicating detrimental effects of life-long increased BDNF in mice, may inform human studies evaluating the role of BDNF functional genetic variations on cognitive abilities and vulnerability to psychiatric disorders.

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References

Lynch G, Rex C, Chen L, Gall C . The substrates of memory: defects, treatments, and enhancement. Eur J Pharmacol. 2008; 585(1):2-13. PMC: 2427007. DOI: 10.1016/j.ejphar.2007.11.082. View

Autry A, Adachi M, Cheng P, Monteggia L . Gender-specific impact of brain-derived neurotrophic factor signaling on stress-induced depression-like behavior. Biol Psychiatry. 2009; 66(1):84-90. PMC: 2734472. DOI: 10.1016/j.biopsych.2009.02.007. View

Schmidt H, Duman R . The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior. Behav Pharmacol. 2007; 18(5-6):391-418. DOI: 10.1097/FBP.0b013e3282ee2aa8. View

Jentsch J, Roth R . The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology. 1999; 20(3):201-25. DOI: 10.1016/S0893-133X(98)00060-8. View

Genoud C, Knott G, Sakata K, Lu B, Welker E . Altered synapse formation in the adult somatosensory cortex of brain-derived neurotrophic factor heterozygote mice. J Neurosci. 2004; 24(10):2394-400. PMC: 6729494. DOI: 10.1523/JNEUROSCI.4040-03.2004. View

Egan M, Kojima M, Callicott J, Goldberg T, Kolachana B, Bertolino A . The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003; 112(2):257-69. DOI: 10.1016/s0092-8674(03)00035-7. View

Isackson P, Huntsman M, Murray K, Gall C . BDNF mRNA expression is increased in adult rat forebrain after limbic seizures: temporal patterns of induction distinct from NGF. Neuron. 1991; 6(6):937-48. DOI: 10.1016/0896-6273(91)90234-q. View

Govindarajan A, Rao B, Nair D, Trinh M, Mawjee N, Tonegawa S . Transgenic brain-derived neurotrophic factor expression causes both anxiogenic and antidepressant effects. Proc Natl Acad Sci U S A. 2006; 103(35):13208-13. PMC: 1559778. DOI: 10.1073/pnas.0605180103. View

Dempster E, Toulopoulou T, McDonald C, Bramon E, Walshe M, Filbey F . Association between BDNF val66 met genotype and episodic memory. Am J Med Genet B Neuropsychiatr Genet. 2005; 134B(1):73-5. DOI: 10.1002/ajmg.b.30150. View

10.

Kanemoto K, Kawasaki J, Tarao Y, Kumaki T, Oshima T, Kaji R . Association of partial epilepsy with brain-derived neurotrophic factor (BDNF) gene polymorphisms. Epilepsy Res. 2003; 53(3):255-8. DOI: 10.1016/s0920-1211(03)00032-9. View

11.

Takahashi M, Kakita A, Futamura T, Watanabe Y, Mizuno M, Sakimura K . Sustained brain-derived neurotrophic factor up-regulation and sensorimotor gating abnormality induced by postnatal exposure to phencyclidine: comparison with adult treatment. J Neurochem. 2006; 99(3):770-80. DOI: 10.1111/j.1471-4159.2006.04106.x. View

12.

Bekinschtein P, Cammarota M, Izquierdo I, Medina J . BDNF and memory formation and storage. Neuroscientist. 2007; 14(2):147-56. DOI: 10.1177/1073858407305850. View

13.

Mizuno M, Yamada K, Olariu A, Nawa H, Nabeshima T . Involvement of brain-derived neurotrophic factor in spatial memory formation and maintenance in a radial arm maze test in rats. J Neurosci. 2000; 20(18):7116-21. PMC: 6772840. View

14.

Monteggia L, Luikart B, Barrot M, Theobold D, Malkovska I, Nef S . Brain-derived neurotrophic factor conditional knockouts show gender differences in depression-related behaviors. Biol Psychiatry. 2006; 61(2):187-97. DOI: 10.1016/j.biopsych.2006.03.021. View

15.

Huang Z, Kirkwood A, Pizzorusso T, Porciatti V, Morales B, Bear M . BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex. Cell. 1999; 98(6):739-55. DOI: 10.1016/s0092-8674(00)81509-3. View

16.

Shmelkov S, Hormigo A, Jing D, Proenca C, Bath K, Milde T . Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive-like behaviors in mice. Nat Med. 2010; 16(5):598-602, 1p following 602. PMC: 2907076. DOI: 10.1038/nm.2125. View

17.

Mu J, Li W, Yao Z, Zhou X . Deprivation of endogenous brain-derived neurotrophic factor results in impairment of spatial learning and memory in adult rats. Brain Res. 1999; 835(2):259-65. DOI: 10.1016/s0006-8993(99)01592-9. View

18.

Shalev I, Lerer E, Israel S, Uzefovsky F, Gritsenko I, Mankuta D . BDNF Val66Met polymorphism is associated with HPA axis reactivity to psychological stress characterized by genotype and gender interactions. Psychoneuroendocrinology. 2008; 34(3):382-8. DOI: 10.1016/j.psyneuen.2008.09.017. View

19.

Murray K, Isackson P, Eskin T, King M, Montesinos S, Abraham L . Altered mRNA expression for brain-derived neurotrophic factor and type II calcium/calmodulin-dependent protein kinase in the hippocampus of patients with intractable temporal lobe epilepsy. J Comp Neurol. 2000; 418(4):411-22. DOI: 10.1002/(sici)1096-9861(20000320)418:4<411::aid-cne4>3.0.co;2-f. View

20.

Papaleo F, Contarino A . Gender- and morphine dose-linked expression of spontaneous somatic opiate withdrawal in mice. Behav Brain Res. 2006; 170(1):110-8. DOI: 10.1016/j.bbr.2006.02.009. View