scholarly journals Deletion of the creatine transporter gene in neonatal, but not adult, mice lead to cognitive deficits

2019 ◽  
Author(s):  
Kenea C. Udobi ◽  
Nicholas Delcimmuto ◽  
Amanda N. Kokenge ◽  
Zuhair I. Abdulla ◽  
Marla K. Perna ◽  
...  
Keyword(s):  
Brain Development ◽  
Cognitive Deficits ◽  
Knockout Mice ◽  
Language Impairment ◽  
Dark Phase ◽  
Creatine Transporter ◽  
Adult Mice ◽  
Object Learning ◽  
Critical Areas ◽  
Severe Intellectual Disability

AbstractCreatine (Cr) is a guanidino compound that provides readily-available phosphate pools for the regeneration of spent ATP. The lack of brain Cr causes moderate to severe intellectual disability, language impairment, and epilepsy. The most prevalent cause of Cr deficiency are mutations in the X-linkedSLC6A8(Creatine transporter; CrT) gene, known as CrT deficiency (CTD). There are no current treatments for CTD and the mechanisms that underlie the cognitive deficits are poorly understood. One of the most critical areas that need to be addressed is if Cr is necessary for brain development. To address this concern, theSlc6a8gene was knocked out in either neonatal (postnatal day (P)5) or adult (P60) mice. The P5 knockout mice showed deficits in the Morris water maze and novel object recognition, while there were no deficits in P60 knockout mice. Interestingly, the P5 knockout mice showed hyperactivity during the dark phase; however, when examining control mice, the effect was due to the administration of tamoxifen from P5-10. Taken together, the results of this study show that Cr is necessary during periods of brain development involved in spatial and object learning. This study also highlights the continued importance of using proper control groups for behavioral testing.Take-home messageThe learning and memory deficits seen in Slc6a8-deficient mice are likely due to the developmental loss of Cr.

scholarly journals Deletion of the creatine transporter gene in neonatal, but not adult, mice leads to cognitive deficits

2019 ◽  
Vol 42 (5) ◽  
pp. 966-974 ◽  
Author(s):  
Kenea C. Udobi ◽  
Nicholas Delcimmuto ◽  
Amanda N. Kokenge ◽  
Zuhair I. Abdulla ◽  
Marla K. Perna ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Transporter Gene ◽  
Creatine Transporter ◽  
Adult Mice

scholarly journals Cognitive impairments from developmental exposure to serotonergic drugs: citalopram and MDMA

2013 ◽  
Vol 16 (6) ◽  
pp. 1383-1394 ◽  
Author(s):  
Tori L. Schaefer ◽  
Curtis E. Grace ◽  
Amanda A. Braun ◽  
Robyn M. Amos-Kroohs ◽  
Devon L. Graham ◽  
...  
Keyword(s):  
Brain Development ◽  
Cognitive Deficits ◽  
System Development ◽  
Third Trimester ◽  
Learning Deficits ◽  
Developmental Exposure ◽  
Target Field ◽  
Field Organization ◽  
Serotonergic Drugs

Abstract We previously showed that developmental 3,4-methylenedioxymethamphetamine (MDMA) treatment induces long-term spatial and egocentric learning and memory deficits and serotonin (5-HT) reductions. During brain development, 5-HT is a neurotrophic factor influencing neurogenesis, synaptogenesis, migration, and target field organization. MDMA (10 mg/kg × 4/d at 2 h intervals) given on post-natal day (PD) 11–20 in rats (a period of limbic system development that approximates human third trimester brain development) induces 50% reductions in 5-HT during treatment and 20% reductions when assessed as adults. To determine whether the 5-HT reduction is responsible for the cognitive deficits, we used citalopram (Cit) pretreatment to inhibit the effects of MDMA on 5-HT reuptake in a companion study. Cit attenuated MDMA-induced 5-HT reductions by 50% (Schaefer et al., 2012). Here we tested whether Cit (5 or 7.5 mg/kg × 2/d) pretreatment attenuates the cognitive effects of MDMA. Within each litter, different offspring were treated on PD11–20 with saline (Sal) + MDMA, Cit + MDMA, Cit + Sal or Sal + Sal. Neither spatial nor egocentric learning/memory was improved by Cit pretreatment. Unexpectedly, Cit + Sal (at both doses) produced spatial and egocentric learning deficits as severe as those caused by Sal + MDMA. These are the first data showing cognitive deficits resulting from developmental exposure to a selective serotonin reuptake inhibitor. These data indicate the need for further research on the long-term safety of antidepressants during pregnancy.

scholarly journals Decreased sensitivity to the anorectic effects of leptin in mice that lack a Pomc-specific neural enhancer

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0244793
Author(s):  
Elisa S. Na ◽  
Daniel D. Lam ◽  
Eva Yokosawa ◽  
Jessica M. Adams ◽  
David P. Olson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Body Weight ◽  
Knockout Mice ◽  
Weight Change ◽  
Body Weight Change ◽  
Dynamic Regulation ◽  
Adult Mice ◽  
Environmental Perturbations ◽  
Mild Obesity ◽  
Over Time

Enhancer redundancy has been postulated to provide a buffer for gene expression against genetic and environmental perturbations. While work in Drosophila has identified functionally overlapping enhancers, work in mammalian models has been limited. Recently, we have identified two partially redundant enhancers, nPE1 and nPE2, that drive proopiomelanocortin gene expression in the hypothalamus. Here we demonstrate that deletion of nPE1 produces mild obesity while knockout of nPE2 has no discernible metabolic phenotypes. Additionally, we show that acute leptin administration has significant effects on nPE1 knockout mice, with food intake and body weight change significantly impacted by peripheral leptin treatment. nPE1 knockout mice became less responsive to leptin treatment over time as percent body weight change increased over 2 week exposure to peripheral leptin. Both Pomc and Agrp mRNA were not differentially affected by chronic leptin treatment however we did see a decrease in Pomc and Agrp mRNA in both nPE1 and nPE2 knockout calorie restricted mice as compared to calorie restricted PBS-treated WT mice. Collectively, these data suggest dynamic regulation of Pomc by nPE1 such that mice with nPE1 knockout become less responsive to the anorectic effects of leptin treatment over time. Our results also support our earlier findings in which nPE2 may only be critical in adult mice that lack nPE1, indicating that these neural enhancers work synergistically to influence metabolism.

That Can't Be Right! What Causes Pragmatic Language Impairment Following Right Hemisphere Damage?

2006 ◽  
Vol 7 (3) ◽  
pp. 202-211 ◽  
Author(s):  
Ingerith Martin ◽  
Skye McDonald
Keyword(s):  
Cognitive Deficits ◽  
Language Impairment ◽  
Right Hemisphere ◽  
Poor Performance ◽  
Weak Central Coherence ◽  
Central Coherence ◽  
Pragmatic Language ◽  
Right Hemisphere Damage ◽  
The Poor ◽  
Pragmatic Language Impairment

AbstractRight hemisphere damage (RHD) following unilateral stroke is often associated with impairment of pragmatic language, specifically, the ability to comprehend inferences that arise from language used in context. Three kinds of cognitive deficits have been proposed to explain the pragmatic deficits in RHD individuals, impaired Theory of Mind (TOM), weak central coherence (CC), and impaired executive function (EF). This study aims to evaluate the explanatory ability of these theories in relation to the comprehension of nonliteral (ironic) jokes versus literal lies. Twenty-one RHD patients and 21 age-matched controls were assessed on tasks tapping TOM, CC processing and general inference ability (EF) and the comprehension of irony. Second-order TOM and EF were found to play a significant role. However, neither construct, either in isolation or combined, completely explained the poor performance of RHD patients on this task compared to control participants.

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 Creatine Transporter (CrT; Slc6a8) Knockout Mice as a Model of Human CrT Deficiency

PLoS ONE ◽  
2011 ◽  
Vol 6 (1) ◽  
pp. e16187 ◽  
Author(s):  
Matthew R. Skelton ◽  
Tori L. Schaefer ◽  
Devon L. Graham ◽  
Ton J. deGrauw ◽  
Joseph F. Clark ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Creatine Transporter

scholarly journals Motor and cognitive deficits in aged tau knockout mice in two background strains

2014 ◽  
Vol 9 (1) ◽  
pp. 29 ◽  
Author(s):  
Peng Lei ◽  
Scott Ayton ◽  
Steve Moon ◽  
Qihao Zhang ◽  
Irene Volitakis ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Knockout Mice

scholarly journals Potential Role of JAK-STAT Signaling Pathway in the Neurogenic-to-Gliogenic Shift in Down Syndrome Brain

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Han-Chung Lee ◽  
Kai-Leng Tan ◽  
Pike-See Cheah ◽  
King-Hwa Ling
Keyword(s):  
Down Syndrome ◽  
Brain Development ◽  
Cell Fate ◽  
Mouse Models ◽  
Neuronal Cell ◽  
Janus Kinase ◽  
Chromosome 21 ◽  
Severe Intellectual Disability ◽  
Stat Signaling

Trisomy of human chromosome 21 in Down syndrome (DS) leads to several phenotypes, such as mild-to-severe intellectual disability, hypotonia, and craniofacial dysmorphisms. These are fundamental hallmarks of the disorder that affect the quality of life of most individuals with DS. Proper brain development involves meticulous regulation of various signaling pathways, and dysregulation may result in abnormal neurodevelopment. DS brain is characterized by an increased number of astrocytes with reduced number of neurons. In mouse models for DS, the pool of neural progenitor cells commits to glia rather than neuronal cell fate in the DS brain. However, the mechanism(s) and consequences of this slight neurogenic-to-gliogenic shift in DS brain are still poorly understood. To date, Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling has been proposed to be crucial in various developmental pathways, especially in promoting astrogliogenesis. Since both human and mouse models of DS brain exhibit less neurons and a higher percentage of cells with astrocytic phenotypes, understanding the role of JAK-STAT signaling in DS brain development will provide novel insight into its role in the pathogenesis of DS brain and may serve as a potential target for the development of effective therapy to improve DS cognition.

Increased cyclin E expression may obviate the role of cyclin D1 during brain development in cyclin D1 knockout mice

2005 ◽  
Vol 92 (5) ◽  
pp. 1281-1284 ◽  
Author(s):  
Zhiguo Chen ◽  
Rui-Sheng Duan ◽  
Yu Zhu ◽  
Ronnie Folkesson ◽  
Chris Albanese ◽  
...  
Keyword(s):  
Brain Development ◽  
Cyclin D1 ◽  
Knockout Mice ◽  
Cyclin E
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