scholarly journals Neuroligin-2 and the tightrope of excitation/inhibition balance in the prefrontal cortex

2016 ◽  
Vol 115 (1) ◽  
pp. 5-7 ◽  
Author(s):  
Alice M. S. Durieux ◽  
Jamie Horder ◽  
Marija M. Petrinovic
Keyword(s):  
Prefrontal Cortex ◽  
Neuropsychiatric Disorders ◽  
Conditional Knockout ◽  
Adhesion Protein ◽  
Inhibition Ratio ◽  
Adult Mice ◽  
Behavioral Impairments

Excitation/inhibition imbalance is implicated in symptoms of neuropsychiatric disorders. We discuss a study by Liang et al. ( Mol Psychiatry 20: 850–859, 2015) demonstrating that the conditional knockout of neuroligin-2, a postsynaptic adhesion protein, in the prefrontal cortex of adult mice results in alterations in inhibitory synaptic properties. However, behavioral impairments emerged prior to the development of detectable changes in excitation/inhibition ratio. This suggests there may be network-specific excitation/inhibition ratios, some of which are more vulnerable to disruption than others.

scholarly journals Dominance Attributions Following Damage to the Ventromedial Prefrontal Cortex

2004 ◽  
Vol 16 (10) ◽  
pp. 1796-1804 ◽  
Author(s):  
Matthew S. Karafin ◽  
Daniel Tranel ◽  
Ralph Adolphs
Keyword(s):  
Prefrontal Cortex ◽  
Cognitive Abilities ◽  
Social Dominance ◽  
Reference Group ◽  
Real Life ◽  
Ventromedial Prefrontal Cortex ◽  
Social Signals ◽  
Focal Lesions ◽  
Normal Individuals ◽  
Behavioral Impairments

Damage to the human ventromedial prefrontal cortex (VM) can result in dramatic and maladaptive changes in social behavior despite preservation of most other cognitive abilities. One important aspect of social cognition is the ability to detect social dominance, a process of attributing from particular social signals another person's relative standing in the social world. To test the role of the VM in making attributions of social dominance, we designed two experiments: one requiring dominance judgments from static pictures of faces, the second requiring dominance judgments from film clips. We tested three demographically matched groups of subjects: subjects with focal lesions in the VM (n = 15), brain-damaged comparison subjects with lesions excluding the VM (n = 11), and a reference group of normal individuals with no history of neurological disease (n = 32). Contrary to our expectation, we found that subjects with VM lesions gave dominance judgments on both tasks that did not differ significantly from those given by the other groups. Despite their grossly normal performance, however, subjects with VM lesions showed more subtle impairments specifically when judging static faces: They were less discriminative in their dominance judgments, and did not appear to make normal use of gender and age of the faces in forming their judgments. The findings suggest that, in the laboratory tasks we used, damage to the VM does not necessarily impair judgments of social dominance, although it appears to result in alterations in strategy that might translate into behavioral impairments in real life.

scholarly journals Systemic Loss of C-terminal Src Kinase Expression Elicits Spontaneous Suppurative Inflammation in Conditional Knockout Mice

2018 ◽  
Vol 55 (2) ◽  
pp. 331-340 ◽  
Author(s):  
Lisa D. Berman-Booty ◽  
Rukiye Eraslan ◽  
Umesh Hanumegowda ◽  
Glenn H. Cantor ◽  
Denise I. Bounous ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Tyrosine Kinases ◽  
Src Kinase ◽  
Inflammatory Cells ◽  
Conditional Knockout ◽  
Tamoxifen Treatment ◽  
Adult Mice ◽  
Proinflammatory Activity ◽  
Gene Excision ◽  
Kinase Expression

C-terminal Src kinase (Csk) is one of the critical negative regulators of the Src family of kinases. The Src family of kinases are nonreceptor tyrosine kinases that regulate inflammation, cell proliferation, motility, and adhesion. To investigate potential histologic lesions associated with systemic loss of Csk gene activity in adult mice, conditional Csk-knockout mice were examined. Cre-mediated systemic excision of Csk induced by tamoxifen treatment resulted in multiorgan inflammation. Specifically, induction of Csk gene excision with three days of tamoxifen treatment resulted in greater than 90% gene excision. Strikingly, these mice developed enteritis that ranged from minimal and suppurative to severe, fibrinonecrosuppurative and hemorrhagic. Other inflammatory lesions included suppurative pneumonia, gastritis, and myocarditis, and increased numbers of inflammatory cells within the hepatic parenchyma. When tamoxifen treatment was reduced from three days to one day in an effort to lower the level of Csk gene excision and limit lesion development, the mice developed severe suppurative to pyogranulomatous pneumonia and minimal to mild suppurative enteritis. Lesions observed secondary to Csk gene excision suggest important roles for Csk in downregulating the proinflammatory activity of the Src family of kinases and limiting neutrophil-mediated inflammation.

scholarly journals APC/CCdh1-Rock2 pathway controls dendritic integrity and memory

2017 ◽  
Vol 114 (17) ◽  
pp. 4513-4518 ◽  
Author(s):  
Verónica Bobo-Jiménez ◽  
María Delgado-Esteban ◽  
Julie Angibaud ◽  
Irene Sánchez-Morán ◽  
Antonio de la Fuente ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Memory Loss ◽  
Neuronal Morphology ◽  
Conditional Knockout ◽  
Anaphase Promoting Complex ◽  
Adult Mice ◽  
Dendritic Network ◽  
Rho Protein ◽  
With Memory

Disruption of neuronal morphology contributes to the pathology of neurodegenerative disorders such as Alzheimer’s disease (AD). However, the underlying molecular mechanisms are unknown. Here, we show that postnatal deletion of Cdh1, a cofactor of the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase in neurons [Cdh1 conditional knockout (cKO)], disrupts dendrite arborization and causes dendritic spine and synapse loss in the cortex and hippocampus, concomitant with memory impairment and neurodegeneration, in adult mice. We found that the dendrite destabilizer Rho protein kinase 2 (Rock2), which accumulates in the brain of AD patients, is an APC/CCdh1 substrate in vivo and that Rock2 protein and activity increased in the cortex and hippocampus of Cdh1 cKO mice. In these animals, inhibition of Rock activity, using the clinically approved drug fasudil, prevented dendritic network disorganization, memory loss, and neurodegeneration. Thus, APC/CCdh1-mediated degradation of Rock2 maintains the dendritic network, memory formation, and neuronal survival, suggesting that pharmacological inhibition of aberrantly accumulated Rock2 may be a suitable therapeutic strategy against neurodegeneration.

Prefrontal cortex rTMS reverses behavioral impairments and differentially activates c-Fos in a mouse model of post-traumatic stress disorder

2019 ◽  
Vol 12 (1) ◽  
pp. 87-95 ◽  
Author(s):  
Marc Legrand ◽  
Romain Troubat ◽  
Bruno Brizard ◽  
Anne-Marie Le Guisquet ◽  
Catherine Belzung ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Mouse Model ◽  
Post Traumatic Stress Disorder ◽  
Traumatic Stress ◽  
Stress Disorder ◽  
Post Traumatic Stress ◽  
Post Traumatic ◽  
Behavioral Impairments

scholarly journals Glial pathology in neuropsychiatric disorders: a brief review

2019 ◽  
Vol 30 (4) ◽  
Author(s):  
Shilpa Borehalli Mayegowda ◽  
Christofer Thomas
Keyword(s):  
Nervous System ◽  
Prefrontal Cortex ◽  
Glial Cells ◽  
Cell Function ◽  
Neuropsychiatric Disorders ◽  
Brain Regions ◽  
Neuronal Function ◽  
Glial Function ◽  
Clinical Conditions ◽  
Stress Models

Abstract Neurons have been considered the major functional entities of the nervous system that are responsible for most of the functions even though glial cells largely outnumber them. However, recent reports have proved that glial cells do not function just like glue in the nervous system but also substantially affect neuronal function and activities, and are significantly involved in the underlying pathobiology of various psychiatric disorders. Dysfunctional astrocytes and degeneration of glial cells are postulated to be critical factors contributing to the aggravation of depressive-like symptoms in humans, which was proved using animal models. Alteration in glial cell function predominantly targets three main brain regions – the prefrontal cortex, limbic areas including the hippocampus, and the amygdala, which have been extensively studied by various researchers across the globe. These studies have postulated that failure in adopting to the changing neurophysiology due to stress will lead to regressive plasticity in the hippocampus and prefrontal cortex, but to progressive plasticity in the amygdala. In this present review, an effort has been made to understand the different alterations in chronic stress models in correlation with clinical conditions, providing evidence on the defective maintenance of glial function and its potential role in the precipitation of neuropsychiatric disorders.

scholarly journals Conditional Deletion of FOXL2 and SMAD4 in Gonadotropes of Adult Mice Causes Isolated FSH Deficiency

Endocrinology ◽  
2018 ◽  
Vol 159 (7) ◽  
pp. 2641-2655 ◽  
Author(s):  
Yining Li ◽  
Gauthier Schang ◽  
Ying Wang ◽  
Xiang Zhou ◽  
Adrien Levasseur ◽  
...  
Keyword(s):  
Ovarian Follicle ◽  
Conditional Knockout ◽  
Tamoxifen Treatment ◽  
Female Sterility ◽  
Follicle Development ◽  
Female Reproduction ◽  
Ovarian Follicle Development ◽  
Adult Mice ◽  
Conditional Deletion ◽  
Driver Line

Abstract The glycoprotein FSH, a product of pituitary gonadotrope cells, regulates ovarian follicle development in females and spermatogenesis in males. FSH is a heterodimer of the common α gonadotropin subunit and the hormone-specific FSHβ subunit (a product of the Fshb gene). Using a conditional knockout approach (Cre-lox), we previously demonstrated that Fshb expression in mice depends on the transcription factors forkhead box L2 (FOXL2) and SMAD4. Deletion of Foxl2 or Smad4 alone led to FSH deficiency, female subfertility, and oligozoospermia in males. Simultaneous deletion of the two genes yielded a greater suppression of FSH and female sterility. The Cre-driver used previously was first active during embryonic development. Therefore, it is unclear whether FOXL2 and SMAD4 play important roles in the development or adult function of gonadotropes, or both. To address this question, we developed a tamoxifen-inducible Cre-driver line, which enabled Foxl2 and Smad4 gene deletions in gonadotropes of adult mice. After tamoxifen treatment, females with previously demonstrated fertility exhibited profound reductions in FSH levels, arrested ovarian follicle development, and sterility. FSH levels were comparably reduced in males 1 or 2 months after treatment; however, spermatogenesis was unaffected. These data indicate that (1) FOXL2 and SMAD4 are necessary to maintain FSH synthesis in gonadotrope cells of adult mice, (2) FSH is essential for female reproduction but appears to be unnecessary for the maintenance of spermatogenesis in adult male mice, and (3) the inducible Cre-driver line developed here provides a powerful tool to interrogate gene function in gonadotrope cells of adult mice.

scholarly journals Essential Role of Cyclin-G–associated Kinase (Auxilin-2) in Developing and Mature Mice

2008 ◽  
Vol 19 (7) ◽  
pp. 2766-2776 ◽  
Author(s):  
Dong-won Lee ◽  
Xiaohong Zhao ◽  
Yang-In Yim ◽  
Evan Eisenberg ◽  
Lois E. Greene
Keyword(s):  
Essential Gene ◽  
Inducible Promoter ◽  
Cre Recombinase ◽  
Conditional Knockout ◽  
Mouse Embryonic Fibroblasts ◽  
Coated Pits ◽  
Embryonic Fibroblasts ◽  
Adult Mice ◽  
Cyclin G

Hsc70 with its cochaperone, either auxilin or GAK, not only uncoats clathrin-coated vesicles but also acts as a chaperone during clathrin-mediated endocytosis. However, because synaptojanin is also involved in uncoating, it is not clear whether GAK is an essential gene. To answer this question, GAK conditional knockout mice were generated and then mated to mice expressing Cre recombinase under the control of the nestin, albumin, or keratin-14 promoters, all of which turn on during embryonic development. Deletion of GAK from brain, liver, or skin dramatically altered the histology of these tissues, causing the mice to die shortly after birth. Furthermore, by expressing a tamoxifen-inducible promoter to express Cre recombinase we showed that deletion of GAK caused lethality in adult mice. Mouse embryonic fibroblasts in which the GAK was disrupted showed a lack of clathrin-coated pits and a complete block in clathrin-mediated endocytosis. We conclude that GAK deletion blocks development and causes lethality in adult animals by disrupting clathrin-mediated endocytosis.

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