scholarly journals BACE inhibitor treatment of mice induces hyperactivity in a Seizure-related gene 6 family dependent manner without altering learning and memory

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
A. Nash ◽  
H. J. M. Gijsen ◽  
B. J. Hrupka ◽  
K. S.-L. Teng ◽  
S. F. Lichtenthaler ◽  
...  
Keyword(s):  
Cognitive Flexibility ◽  
Dendritic Spine ◽  
Knockout Mice ◽  
Cortical Neurons ◽  
Dependent Manner ◽  
Spine Density ◽  
Related Gene ◽  
Wild Type ◽  
Bace Inhibitor ◽  
Inhibitor Treatment

AbstractBACE inhibitors, which decrease BACE1 (β-secretase 1) cleavage of the amyloid precursor protein, are a potential treatment for Alzheimer’s disease. Clinical trials using BACE inhibitors have reported a lack of positive effect on patient symptoms and, in some cases, have led to increased adverse events, cognitive worsening and hippocampal atrophy. A potential drawback of this strategy is the effect of BACE inhibition on other BACE1 substrates such as Seizure-related gene 6 (Sez6) family proteins which are known to have a role in neuronal function. Mice were treated with an in-diet BACE inhibitor for 4–8 weeks to achieve a clinically-relevant level of amyloid-β40 reduction in the brain. Mice underwent behavioural testing and postmortem analysis of dendritic spine number and morphology with Golgi-Cox staining. Sez6 family triple knockout mice were tested alongside wild-type mice to identify whether any effects of the treatment were due to altered cleavage of Sez6 family proteins. Wild-type mice treated with BACE inhibitor displayed hyperactivity on the elevated open field, as indicated by greater distance travelled, but this effect was not observed in treated Sez6 triple knockout mice. BACE inhibitor treatment did not lead to significant changes in spatial or fear learning, reference memory, cognitive flexibility or anxiety in mice as assessed by the Morris water maze, context fear conditioning, or light–dark box tests. Chronic BACE inhibitor treatment reduced the density of mushroom-type spines in the somatosensory cortex, regardless of genotype, but did not affect steady-state dendritic spine density or morphology in the CA1 region of the hippocampus. Chronic BACE inhibition for 1–2 months in mice led to increased locomotor output but did not alter memory or cognitive flexibility. While the mechanism underlying the treatment-induced hyperactivity is unknown, the absence of this response in Sez6 triple knockout mice indicates that blocking ectodomain shedding of Sez6 family proteins is a contributing factor. In contrast, the decrease in mature spine density in cortical neurons was not attributable to lack of shed Sez6 family protein ectodomains. Therefore, other BACE1 substrates are implicated in this effect and, potentially, in the cognitive decline in longer-term chronically treated patients.

scholarly journals BACE Inhibitor Treatment in Mice Induces Hyperactivity in a Seizure-Related Gene 6 Family Protein Dependent Manner but Does Not alter Spatial Learning and Reference Memory

2021 ◽  
Author(s):  
A. Nash ◽  
H. J. M. Gijsen ◽  
B. J. Hrupka ◽  
K. S-L. Teng ◽  
S. F. Lichtenthaler ◽  
...  
Keyword(s):  
Cognitive Flexibility ◽  
Dendritic Spine ◽  
Knockout Mice ◽  
Reference Memory ◽  
Spine Density ◽  
Related Gene ◽  
Wild Type ◽  
Bace Inhibitor ◽  
Family Protein ◽  
Inhibitor Treatment

Abstract BackgroundBACE inhibitors, which decrease BACE1 (β-secretase 1) cleavage of the amyloid precursor protein, are a potential treatment for Alzheimer’s disease. Clinical trials using BACE inhibitors have reported a lack of positive effect on patient symptoms and, in some cases, have led to increased adverse events, cognitive worsening and hippocampal atrophy. A potential drawback of this strategy is the effect of BACE inhibition on other BACE1 substrates such as Seizure-related gene 6 (Sez6) family proteins which are known to have a role in neuronal function.MethodsMice were treated with an in-diet BACE inhibitor for 4-8 weeks to achieve a clinically-relevant level of amyloid-β40 reduction in the brain. Mice underwent behavioural testing and postmortem analysis of dendritic spine number and morphology with Golgi-Cox staining. Sez6 family triple knockout mice were tested alongside wild-type mice to identify whether any effects of the treatment were due to altered cleavage of Sez6 family proteins.ResultsWild-type mice treated with BACE inhibitor displayed hyperactivity on the elevated open field, as indicated by greater distance travelled, but this effect was not observed in treated Sez6 triple knockout mice. BACE inhibitor treatment did not lead to significant changes in spatial or fear learning, reference memory, cognitive flexibility or anxiety in mice as assessed by the Morris water maze, context fear conditioning, or light-dark box tests. Chronic BACE inhibitor treatment reduced the density of mushroom-type spines in the somatosensory cortex, regardless of genotype, but did not affect steady-state dendritic spine density or morphology in the CA1 region of the hippocampus. ConclusionsChronic BACE inhibition for 1-2 months in mice led to increased locomotor output but did not alter memory or cognitive flexibility. While the mechanism underlying the treatment-induced hyperactivity is unknown, the absence of this response in Sez6 triple knockout mice indicates that blocking ectodomain shedding of Sez6 family proteins is a contributing factor. In contrast, the decrease in mature spine density in cortical neurons was not attributable to lack of shed Sez6 family protein ectodomains. Therefore, other BACE1 substrates are implicated in this effect and, potentially, in the cognitive decline in longer-term chronically treated patients.

scholarly journals Electroacupuncture Stimulation at CV12 Inhibits Gastric Motility via TRPV1 Receptor

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Zhi Yu ◽  
Xin Cao ◽  
Youbing Xia ◽  
Binbin Ren ◽  
Hong Feng ◽  
...  
Keyword(s):  
Gastric Motility ◽  
Knockout Mice ◽  
Functional Gastrointestinal Disorders ◽  
Inhibitory Effect ◽  
Gastrointestinal Disorders ◽  
Dependent Manner ◽  
Wild Type ◽  
Trpv1 Receptor ◽  
Alternative Approaches ◽  
Trpv1 Antagonist

Gastric dysmotility is one of the major pathophysiological factors in functional gastrointestinal disorders. Acupuncture, as one of the alternative approaches, is efficacious in the treatment of gastrointestinal motility disorders; however, the mechanism underlying its action is unclear. In the present study, we used both capsazepine, a TRPV1 antagonist, and TRPV1 knockout mice. Animals were divided into wild-type group (WT), capsazepine injection group (CZP, 0.5 mg/kg, i.p.), and TRPV1 knockout mice group (TRPV1−/−). Each of these three groups was divided into three subgroups, which were subjected to EA stimulation at acupoint Zhongwan (CV12) at a different intensity (1, 2, or 4 mA). We demonstrated that electroacupuncture at Zhongwan (CV12) markedly inhibited gastric motility at 2 and 4 mA in an intensity-dependent manner in wild-type mice. The inhibitory effect was also observed in capsazepine-injected and TRPV1−/−mice but was no longer intensity dependent, indicating that TRPV1 is partially involved in the electroacupuncture-mediated modulation of gastric motility.

scholarly journals TheGαoActivator Mastoparan-7 Promotes Dendritic Spine Formation in Hippocampal Neurons

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Valerie T. Ramírez ◽  
Eva Ramos-Fernández ◽  
Nibaldo C. Inestrosa
Keyword(s):  
Protein Kinase ◽  
Dendritic Spine ◽  
Hippocampal Neurons ◽  
Biological Effects ◽  
Critical Role ◽  
Head Width ◽  
Dependent Manner ◽  
Spine Density ◽  
Dendritic Spine Density

Mastoparan-7 (Mas-7), an analogue of the peptide mastoparan, which is derived from wasp venom, is a direct activator ofPertussis toxin-(PTX-) sensitive G proteins. Mas-7 produces several biological effects in different cell types; however, little is known about how Mas-7 influences mature hippocampal neurons. We examined the specific role of Mas-7 in the development of dendritic spines, the sites of excitatory synaptic contact that are crucial for synaptic plasticity. We report here that exposure of hippocampal neurons to a low dose of Mas-7 increases dendritic spine density and spine head width in a time-dependent manner. Additionally, Mas-7 enhances postsynaptic density protein-95 (PSD-95) clustering in neurites and activatesGαosignaling, increasing the intracellular Ca2+concentration. To define the role of signaling intermediates, we measured the levels of phosphorylated protein kinase C (PKC), c-Jun N-terminal kinase (JNK), and calcium-calmodulin dependent protein kinase IIα(CaMKIIα) after Mas-7 treatment and determined that CaMKII activation is necessary for the Mas-7-dependent increase in dendritic spine density. Our results demonstrate a critical role forGαosubunit signaling in the regulation of synapse formation.

scholarly journals Decreased dendritic spine density and abnormal spine morphology in Fyn knockout mice

2011 ◽  
Vol 1415 ◽  
pp. 96-102 ◽  
Author(s):  
Lenard W. Babus ◽  
Elizabeth M. Little ◽  
Kathleen E. Keenoy ◽  
S. Sakura Minami ◽  
Eric Chen ◽  
...  
Keyword(s):  
Dendritic Spine ◽  
Knockout Mice ◽  
Spine Density ◽  
Spine Morphology ◽  
Dendritic Spine Density

Vigilance state-dependent attenuation of hypercapnic chemoreflex and exaggerated sleep apnea in orexin knockout mice

2007 ◽  
Vol 102 (1) ◽  
pp. 241-248 ◽  
Author(s):  
Akira Nakamura ◽  
Wei Zhang ◽  
Masashi Yanagisawa ◽  
Yasuichiro Fukuda ◽  
Tomoyuki Kuwaki
Keyword(s):  
Rem Sleep ◽  
Knockout Mice ◽  
Slow Wave Sleep ◽  
Ventilatory Response ◽  
Control Of Breathing ◽  
Dependent Manner ◽  
Wild Type ◽  
Vigilance State ◽  
State Dependent ◽  
Respiratory Parameters

Exogenous administration of orexin can promote wakefulness and respiration. Here we examined whether intrinsic orexin participates in the control of breathing in a vigilance state-dependent manner. Ventilation was recorded together with electroencephalography and electromyography for 6 h during the daytime in prepro-orexin knockout mice (ORX-KO) and wild-type (WT) littermates. Respiratory parameters were separately determined during quiet wakefulness (QW), slow-wave sleep (SWS), or rapid eye movement (REM) sleep. Basal ventilation was normal in ORX-KO, irrespective of vigilance states. The hypercapnic ventilatory response during QW in ORX-KO (0.19 ± 0.01 ml·min−1·g−1·%CO2−1) was significantly smaller than that in WT mice (0.38 ± 0.04 ml·min−1·g−1·%CO2−1), whereas the responses during SWS and REM in ORX-KO were comparable to those in WT mice. Hypoxic responses during wake and sleep periods were not different between the genotypes. Spontaneous but not postsigh sleep apneas were more frequent in ORX-KO than in WT littermates during both SWS and REM sleep. Our findings suggest that orexin plays a crucial role both in CO2 sensitivity during wakefulness and in preserving ventilation stability during sleep.

scholarly journals Chemokine Receptor CXCR-2 Initiates Atrial Fibrillation by Triggering Monocyte Mobilization in Mice

Hypertension ◽  
2020 ◽  
Vol 76 (2) ◽  
pp. 381-392 ◽  
Author(s):  
Yun-Long Zhang ◽  
Hua-Jun Cao ◽  
Xiao Han ◽  
Fei Teng ◽  
Chen Chen ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Bone Marrow ◽  
Chemokine Receptor ◽  
Knockout Mice ◽  
Bone Marrow Cells ◽  
Atrial Remodeling ◽  
Dependent Manner ◽  
Ang Ii ◽  
Wild Type ◽  
Chemokine Ligands

Atrial fibrillation (AF) is frequently associated with increased inflammatory response characterized by infiltration of monocytes/macrophages. The chemokine receptor CXCR-2 is a critical regulator of monocyte mobilization in hypertension and cardiac remodeling, but it is not known whether CXCR-2 is involved in the development of hypertensive AF. AF was induced by infusion of Ang II (angiotensin II; 2000 ng/kg per minute) for 3 weeks in male C57BL/6 wild-type mice, CXCR-2 knockout mice, bone marrow-reconstituted chimeric mice, and mice treated with the CXCR-2 inhibitor SB225002. Microarray analysis revealed that 4 chemokine ligands of CXCR-2 were significantly upregulated in the atria during 3 weeks of Ang II infusion. CXCR-2 expression and the number of CXCR2 + immune cells markedly increased in Ang II–infused atria in a time-dependent manner. Moreover, Ang II–infused wild-type mice had increased blood pressure, AF inducibility, atrial diameter, fibrosis, infiltration of macrophages, and superoxide production compared with saline-treated wild-type mice, whereas these effects were significantly attenuated in CXCR-2 knockout mice and wild-type mice transplanted with CXCR-2-deficient bone marrow cells or treated with SB225002. Moreover, circulating blood CXCL-1 levels and CXCR2 + monocyte counts were higher and associated with AF in human patients (n=31) compared with sinus rhythm controls (n=31). In summary, this study identified a novel role for CXCR-2 in driving monocyte infiltration of the atria, which accelerates atrial remodeling and AF after hypertension. Blocking CXCR-2 activation may serve as a new therapeutic strategy for AF.

scholarly journals Fingolimod Modulates Dendritic Architecture in a BDNF-Dependent Manner

2020 ◽  
Vol 21 (9) ◽  
pp. 3079 ◽  
Author(s):  
Abhisarika Patnaik ◽  
Eleonora Spiombi ◽  
Angelisa Frasca ◽  
Nicoletta Landsberger ◽  
Marta Zagrebelsky ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Rett Syndrome ◽  
Cortical Neurons ◽  
Hippocampal Neurons ◽  
Neurological Diseases ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Spine Density ◽  
Neuronal Structure ◽  
Cellular Mechanisms

The brain-derived neurotrophic factor (BDNF) plays crucial roles in both the developing and mature brain. Moreover, alterations in BDNF levels are correlated with the cognitive impairment observed in several neurological diseases. Among the different therapeutic strategies developed to improve endogenous BDNF levels is the administration of the BDNF-inducing drug Fingolimod, an agonist of the sphingosine-1-phosphate receptor. Fingolimod treatment was shown to rescue diverse symptoms associated with several neurological conditions (i.e., Alzheimer disease, Rett syndrome). However, the cellular mechanisms through which Fingolimod mediates its BDNF-dependent therapeutic effects remain unclear. We show that Fingolimod regulates the dendritic architecture, dendritic spine density and morphology of healthy mature primary hippocampal neurons. Moreover, the application of Fingolimod upregulates the expression of activity-related proteins c-Fos and pERK1/2 in these cells. Importantly, we show that BDNF release is required for these actions of Fingolimod. As alterations in neuronal structure underlie cognitive impairment, we tested whether Fingolimod application might prevent the abnormalities in neuronal structure typical of two neurodevelopmental disorders, namely Rett syndrome and Cdk5 deficiency disorder. We found a significant rescue in the neurite architecture of developing cortical neurons from Mecp2 and Cdkl5 mutant mice. Our study provides insights into understanding the BDNF-dependent therapeutic actions of Fingolimod.

Roles of prostaglandin E2-EP1 receptor signaling in regulation of gastric motor activity and emptying

2010 ◽  
Vol 299 (5) ◽  
pp. G1078-G1086 ◽  
Author(s):  
Sumito Mizuguchi ◽  
Takashi Ohno ◽  
Youichiro Hattori ◽  
Takako Ae ◽  
Tsutomu Minamino ◽  
...  
Keyword(s):  
Gastric Emptying ◽  
Motor Activity ◽  
Continuous Infusion ◽  
Knockout Mice ◽  
Smooth Muscles ◽  
Dependent Manner ◽  
Wild Type ◽  
Gastric Artery ◽  
Myoelectrical Activity ◽  
Gastric Motor Activity

It is widely accepted that the inhibition of gastric motor activity as well as the maintenance of gastric mucosal blood flow and mucous secretion are important for the homeostasis of the gastric mucosa. The present study was performed to ascertain whether or not endogenous PGs, which can protect the stomach from noxious stimuli, affect gastric motor activity and emptying. The myoelectrical activity of rat gastric smooth muscle was increased at intragastric pressures of over 2 cmH2O. Replacement of intragastric physiological saline with 1 M NaCl solution significantly increased PGI2 and PGE2 in stomach and suppressed the myoelectrical activity under a pressure of 2 cmH2O by 70%. Indomethacin inhibited the suppression of myoelectrical activity by 1 M NaCl. The myoelectrical activity under a pressure of 2 cmH2O was suppressed by continuous infusion of a selective EP1 agonist (ONO-DI-004, 3–100 nmol·kg−1·min−1) into the gastric artery in a dose-dependent manner, but not by that of the PGI receptor agonist beraprost sodium (100 nmol·kg−1·min−1). Suppression of myoelectrical activity with 1 M NaCl was inhibited by continuous infusion of a selective EP1 antagonist (ONO-8711, 100 nmol·kg−1·min−1) into the gastric artery. Furthermore, gastric emptying was tested in EP1 knockout mice and their wild-type counterparts. Gastric emptying was strongly suppressed with intragastric 1 M NaCl in wild-type mice, but this 1 M NaCl-induced suppression was not seen in EP1 knockout mice. These results suggest that PGE2-EP1 signaling has crucial roles in suppression of myoelectrical activity of gastric smooth muscles and inhibition of gastric emptying and that EP1 is an obvious target for drugs that control gastric emptying.

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