Brain-derived neurotrophic factor: a biomarker for obsessive-compulsive disorder?

Oliveira‐Maia, Albino J.; Castro-Rodrigues, Pedro

doi:10.3389/fnins.2015.00134

Cited by 10 publications

(8 citation statements)

References 34 publications

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“… 16 , 17 Alterations in BDNF plasma levels are indicative of various psychiatric disorders 14 and may also be associated with OCD. 18 Genetic variations of the NTRK2 gene encoding TrkB were suggested to contribute to OCD in humans, however, the pathomechanism is unknown. 19 The impact of BDNF and its receptor TrkB on anxiety-related disorders has been investigated in mouse models but this also revealed contradictory results.…”

Section: Introductionmentioning

confidence: 99%

OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB/ERK-MAPK signaling as a result of SPRED2 deficiency

et al. 2017

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Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disease affecting about 2% of the general population. It is characterized by persistent intrusive thoughts and repetitive ritualized behaviors. While gene variations, malfunction of cortico-striato-thalamo-cortical (CSTC) circuits, and dysregulated synaptic transmission have been implicated in the pathogenesis of OCD, the underlying mechanisms remain largely unknown. Here we show that OCD-like behavior in mice is caused by deficiency of SPRED2, a protein expressed in various brain regions and a potent inhibitor of Ras/ERK-MAPK signaling. Excessive self-grooming, reflecting OCD-like behavior in rodents, resulted in facial skin lesions in SPRED2 knockout (KO) mice. This was alleviated by treatment with the selective serotonin reuptake inhibitor fluoxetine. In addition to the previously suggested involvement of cortico-striatal circuits, electrophysiological measurements revealed altered transmission at thalamo-amygdala synapses and morphological differences in lateral amygdala neurons of SPRED2 KO mice. Changes in synaptic function were accompanied by dysregulated expression of various pre- and postsynaptic proteins in the amygdala. This was a result of altered gene transcription and triggered upstream by upregulated tropomyosin receptor kinase B (TrkB)/ERK-MAPK signaling in the amygdala of SPRED2 KO mice. Pathway overactivation was mediated by increased activity of TrkB, Ras, and ERK as a specific result of SPRED2 deficiency and not elicited by elevated brain-derived neurotrophic factor levels. Using the MEK inhibitor selumetinib, we suppressed TrkB/ERK-MAPK pathway activity in vivo and reduced OCD-like grooming in SPRED2 KO mice. Altogether, this study identifies SPRED2 as a promising new regulator, TrkB/ERK-MAPK signaling as a novel mediating mechanism, and thalamo-amygdala synapses as critical circuitry involved in the pathogenesis of OCD.

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Section: Introductionmentioning

confidence: 99%

OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB/ERK-MAPK signaling as a result of SPRED2 deficiency

et al. 2017

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“…In addition, our data showed that Met at the dose of 10 mg/kg increased BDNF levels compared with the OVX group. Furthermore, sex hormones could have modulating effects on neuropathic factors, such as BDNF . Hui et al, in a study on female blood samples reported that the gradual reduction of estradiol in women was associated with a decrease in serum BDNF levels .…”

Section: Discussionmentioning

confidence: 68%

“…Previously published studies have shown that Met supplements increase longevity in Caenorhabditis elegans and mice. Recently, it was found that Met (50 mg/d) has increased the mean life expectancy of Caenorhabditis elegans . In another study, it was reported that Met increases life span and delays the first tumor detection in female SHR mice .…”

Section: Discussionmentioning

confidence: 99%

Pro‐neurocognitive and anti‐sarcopenic benefits of one‐year metformin therapy in ovariectomized aged mice

Zakeri

Fatemi

Kaeidi

et al. 2019

Clin Exp Pharma Physio

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Health promotion and healthy nutrition significantly increased life expectancy around the world. Aging is associated with an increase in age-related diseases. The use of metformin (Met) as an anti-aging drug has recently been proposed based on its widespread use in clinical practice. Reports have shown that Met acts as an antiaging agent. In this study, the effects of long-term, 1 year, Met administration on aging-related behaviors and longevity in ovariectomized mice was studied. Met (1 and 10 mg/kg, daily) was administered orally in ovariectomized mice. The anxiety-like behavior, working memory, and physical strength were measured through elevated plus maze, Y-maze, vertical grid holding, and the obligatory swimming capacity tests.Brains were harvested to measure brain-derived neurotrophic factor (BDNF) level.Also, the Kaplan-Meier survival curves were used to show differences and similarities in survival patterns. Met (10 mg/kg) decreased anxiety-like behaviors as well as increased muscle strength and working memory in the ovariectomized mice. Moreover, Met increased the physical strength and longevity as well as the level of BDNF in the ovariectomized mice. Our results indicate that Met administration can be an effective strategy for having a healthy aging in the absence of female gonadal hormones and reverses deleterious effects of ovariectomy-induced aging possibly through BDNF. K E Y W O R D Saging, brain-derived neurotrophic factor, metformin, ovariectomy

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“…Indeed, as with animal models of neuropsychiatric disorders, the predictive validity of neuropsychiatric biomarkers is still to be established (Chen-Plotkin, 2014;Hyman, 2007;Jablensky, 2013). For example, there are any number of proposed biomarkers for psychiatric disorders (Gururajan et al, 2016;Javitt et al, 2008;Kapczinski et al, 2009;Oliveira-Maia and Castro-Rodrigues, 2015). Brain derived neurotrpphic factor (BDNF), for example has long been associated with mood disorders such as major depressive disorder (Hashimoto, 2010).…”

Section: Biomarkersmentioning

confidence: 99%

“…Brain derived neurotrpphic factor (BDNF), for example has long been associated with mood disorders such as major depressive disorder (Hashimoto, 2010). The biomarker specificity of BDNF is not clear, however, as it is also associated with anxiety and obsessive-compulsive disorder (Oliveira-Maia and Castro-Rodrigues, 2015;Suliman et al, 2013). Furthermore, issues regarding the source of tissue selected for BDNF sampling, for example, discrete categorization of subjects in clinical studies, and experimental procedures used in animal models, all may account for conflicting results in clinical and preclinical studies of the role of BDNF for depression (Gururajan et al, 2016).…”

Section: Biomarkersmentioning

confidence: 99%

Aligning physiology with psychology: Translational neuroscience in neuropsychiatric drug discovery

McArthur¹

2017

Neuroscience & Biobehavioral Reviews

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Brain-derived neurotrophic factor: a biomarker for obsessive-compulsive disorder?

Cited by 10 publications

References 34 publications

OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB/ERK-MAPK signaling as a result of SPRED2 deficiency

OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB/ERK-MAPK signaling as a result of SPRED2 deficiency

Pro‐neurocognitive and anti‐sarcopenic benefits of one‐year metformin therapy in ovariectomized aged mice

Aligning physiology with psychology: Translational neuroscience in neuropsychiatric drug discovery

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