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.

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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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Desmond, Nancy L
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New York University
Schools of Medicine
New York
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Jing, Deqiang; Lee, Francis S; Ninan, Ipe (2017) The BDNF Val66Met polymorphism enhances glutamatergic transmission but diminishes activity-dependent synaptic plasticity in the dorsolateral striatum. Neuropharmacology 112:84-93
Galvin, Christopher; Lee, Francis S; Ninan, Ipe (2015) Alteration of the Centromedial Amygdala Glutamatergic Synapses by the BDNF Val66Met Polymorphism. Neuropsychopharmacology 40:2269-77
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
Parkhurst, Christopher N; Yang, Guang; Ninan, Ipe et al. (2013) Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155:1596-609