The neurobiological basis of the high prevalence of affective disorders in women is not well understood. One potential mechanism for sex-dependent modification of affective behaviors is an interaction with genetic risk factors. Brain-derived neurotrophic factor (BDNF) has been shown to exert sexually dimorphic effect on affective behaviors. We propose to explore the effect of a potential interaction between a common single nucleotide polymorphism in the BDNF gene, the Val66Met polymorphism, and sex on synaptic function in the infralimbic medial prefrontal cortex. The BDNF Val66Met polymorphism has been implicated in cognitive dysfunctions and several neuropsychiatric disorders including anxiety and depression. Also, this polymorphism is known to modify brain functions in a sex-dependent manner. BDNFMet/Met mice, a variant BDNF Val66Met knock-in mouse, showed anxiety-like behavior and deficit in fear extinction, a form of inhibitory learning that suppresses a previously learned fear. BDNFMet/Met mice also showed a sex-dependent modification of glutamatergic neurotransmission in the infralimbic medial prefrontal cortex. The BDNF Val66Met is known to interact with estradiol and alter brain function. Therefore, we hypothesize that the Val66Met polymorphism exacerbates deficits in IL-mPFC synaptic function by its interaction with estradiol. We will test this hypothesis by analyzing glutamatergic synaptic transmission in the IL-mPFC layer V pyramidal neurons from male and female [proestrus (high-estradiol), diestrus (low-estradiol) and ovariectomized] BDNFMet/Met and wild-type mice. In addition to the effect on synaptic function, the Val66Met could affect intrinsic properties of IL-mPFC neurons in a sex-specific fashion. Therefore, we will also study whether an interaction between Val66Met and estradiol modifies intrinsic properties of the IL-mPFC layer V pyramidal neurons. By undertaking this study, we expect to understand the interaction of BDNF Val66Met polymorphism and sex in the IL-mPFC and its involvement in sexual dimorphism in affective behaviors.

Public Health Relevance

The prevalence of affective disorders is approximately twice in women compared to men. However, the neurobiological basis of this sex-dependent effect is unknown. In the current proposal, we will investigate the effect of interaction between a common single nucleotide polymorphism in the BDNF gene and sex on synaptic function in the infralimbic medial prefrontal cortex, a brain region believed to be involved in the regulation of affective behaviors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
3R01MH096899-01A1S1
Application #
8720894
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Desmond, Nancy L
Project Start
2013-09-23
Project End
2015-08-31
Budget Start
2013-09-23
Budget End
2015-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$64,156
Indirect Cost
$26,306
Name
New York University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Ninan, Ipe (2014) Synaptic regulation of affective behaviors; role of BDNF. Neuropharmacology 76 Pt C:684-95
Galvin, Christopher; Ninan, Ipe (2014) Regulation of the mouse medial prefrontal cortical synapses by endogenous estradiol. Neuropsychopharmacology 39:2086-94
Scheele, Dirk; Kendrick, Keith M; Khouri, Christoph et al. (2014) An oxytocin-induced facilitation of neural and emotional responses to social touch correlates inversely with autism traits. Neuropsychopharmacology 39:2078-85