scholarly journals GSK3β inhibition restores cortical gamma oscillation and cognitive behavior in a mouse model of NMDA receptor hypofunction relevant to schizophrenia

2020 ◽  
Vol 45 (13) ◽  
pp. 2207-2218
Author(s):  
Kazuhito Nakao ◽  
Mahendra Singh ◽  
Kiran Sapkota ◽  
Bailey C. Hagler ◽  
Robert N. Hunter ◽  
...  
Keyword(s):  
Working Memory ◽  
Mouse Model ◽  
Spatial Working Memory ◽  
Gamma Oscillations ◽  
Gamma Oscillation ◽  
Mutant Mice ◽  
Patch Clamp Recording ◽  
Behavioral Deficits ◽  
Gamma Power ◽  
Sensory Evoked

Abstract Cortical gamma oscillations are believed to be involved in mental processes which are disturbed in schizophrenia. For example, the magnitudes of sensory-evoked oscillations, as measured by auditory steady-state responses (ASSRs) at 40 Hz, are robustly diminished, whereas the baseline gamma power is enhanced in schizophrenia. Such dual gamma oscillation abnormalities are also present in a mouse model of N-methyl-D-aspartate receptor hypofunction (Ppp1r2cre/Grin1 knockout mice). However, it is unclear whether the abnormal gamma oscillations are associated with dysfunction in schizophrenia. We found that glycogen synthase kinase-3 (GSK3) is overactivated in corticolimbic parvalbumin-positive GABAergic interneurons in Grin1 mutant mice. Here we addressed whether GSK3β inhibition reverses both abnormal gamma oscillations and behavioral deficits with high correlation by pharmacological and genetic approach. We demonstrated that the paralog selective-GSK3β inhibitor, but not GSK3α inhibitor, normalizes the diminished ASSRs, excessive baseline gamma power, and deficits in spatial working memory and prepulse inhibition (PPI) of acoustic startle in Grin1 mutant mice. Cell-type specific GSK3B knockdown, but not GSK3A knockdown, also reversed abnormal gamma oscillations and behavioral deficits. Moreover, GSK3B knockdown, but not GSK3A knockdown, reverses the mutants’ in vivo spike synchrony deficits. Finally, ex vivo patch-clamp recording from pairs of neighboring cortical pyramidal neurons showed a reduction of synchronous spontaneous inhibitory-postsynaptic-current events in mutants, which was reversed by GSK3β inhibition genetically and pharmacologically. Together, GSK3β inhibition in corticolimbic interneurons ameliorates the deficits in spatial working memory and PPI, presumably by restoration of synchronous GABA release, synchronous spike firing, and evoked-gamma power increase with lowered baseline power.

scholarly journals Impaired spike-gamma coupling of area CA3 fast-spiking interneurons as the earliest functional impairment in the AppNL-G-F mouse model of Alzheimer’s disease

2021 ◽  
Author(s):  
Luis Enrique Arroyo-García ◽  
Arturo G. Isla ◽  
Yuniesky Andrade-Talavera ◽  
Hugo Balleza-Tapia ◽  
Raúl Loera-Valencia ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mouse Model ◽  
Functional Impairment ◽  
Amyloid Β ◽  
Gamma Oscillations ◽  
Gamma Oscillation ◽  
Gamma Rhythm ◽  
Fast Spiking

AbstractIn Alzheimer’s disease (AD) the accumulation of amyloid-β (Aβ) correlates with degradation of cognition-relevant gamma oscillations. The gamma rhythm relies on proper neuronal spike-gamma coupling, specifically of fast-spiking interneurons (FSN). Here we tested the hypothesis that decrease in gamma power and FSN synchrony precede amyloid plaque deposition and cognitive impairment in AppNL-G-F knock-in mice (AppNL-G-F). The aim of the study was to evaluate the amyloidogenic pathology progression in the novel AppNL-G-F mouse model using in vitro electrophysiological network analysis. Using patch clamp of FSNs and pyramidal cells (PCs) with simultaneous gamma oscillation recordings, we compared the activity of the hippocampal network of wild-type mice (WT) and the AppNL-G-F mice at four disease stages (1, 2, 4, and 6 months of age). We found a severe degradation of gamma oscillation power that is independent of, and precedes Aβ plaque formation, and the cognitive impairment reported previously in this animal model. The degradation correlates with increased Aβ1-42 concentration in the brain. Analysis on the cellular level showed an impaired spike-gamma coupling of FSN from 2 months of age that correlates with the degradation of gamma oscillations. From 6 months of age PC firing becomes desynchronized also, correlating with reports in the literature of robust Aβ plaque pathology and cognitive impairment in the AppNL-G-F mice. This study provides evidence that impaired FSN spike-gamma coupling is one of the earliest functional impairment caused by the amyloidogenic pathology progression likely is the main cause for the degradation of gamma oscillations and consequent cognitive impairment. Our data suggests that therapeutic approaches should be aimed at restoring normal FSN spike-gamma coupling and not just removal of Aβ.

scholarly journals Phospholamban Knockout Breaks Arrhythmogenic Ca 2+ Waves and Suppresses Catecholaminergic Polymorphic Ventricular Tachycardia in Mice

2013 ◽  
Vol 113 (5) ◽  
pp. 517-526 ◽  
Author(s):  
Yunlong Bai ◽  
Peter P. Jones ◽  
Jiqing Guo ◽  
Xiaowei Zhong ◽  
Robert B. Clark ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Mouse Model ◽  
Ventricular Myocytes ◽  
Mutant Mice ◽  
Polymorphic Ventricular Tachycardia ◽  
Patch Clamp Recording ◽  
Plasmic Reticulum ◽  
Paradoxical Effects ◽  
Triggered Arrhythmias ◽  
The Impact

Rationale : Phospholamban (PLN) is an inhibitor of cardiac sarco(endo)plasmic reticulum Ca 2+ ATPase. PLN knockout (PLN-KO) enhances sarcoplasmic reticulum Ca 2+ load and Ca 2+ leak. Conversely, PLN-KO accelerates Ca 2+ sequestration and aborts arrhythmogenic spontaneous Ca 2+ waves (SCWs). An important question is whether these seemingly paradoxical effects of PLN-KO exacerbate or protect against Ca 2+ -triggered arrhythmias. Objective : We investigate the impact of PLN-KO on SCWs, triggered activities, and stress-induced ventricular tachyarrhythmias (VTs) in a mouse model of cardiac ryanodine-receptor (RyR2)-linked catecholaminergic polymorphic VT. Methods and Results : We generated a PLN-deficient, RyR2-mutant mouse model (PLN −/− /RyR2-R4496C +/− ) by crossbreeding PLN-KO mice with catecholaminergic polymorphic VT–associated RyR2-R4496C mutant mice. Ca 2+ imaging and patch-clamp recording revealed cell-wide propagating SCWs and triggered activities in RyR2-R4496C +/− ventricular myocytes during sarcoplasmic reticulum Ca 2+ overload. PLN-KO fragmented these cell-wide SCWs into mini-waves and Ca 2+ sparks and suppressed the triggered activities evoked by sarcoplasmic reticulum Ca 2+ overload. Importantly, these effects of PLN-KO were reverted by partially inhibiting sarco(endo)plasmic reticulum Ca 2+ ATPase with 2,5-di-tert-butylhydroquinone. However, Bay K, caffeine, or Li + failed to convert mini-waves to cell-wide SCWs in PLN −/− /RyR2-R4496C +/− ventricular myocytes. Furthermore, ECG analysis showed that PLN-KO mice are not susceptible to stress-induced VTs. On the contrary, PLN-KO protected RyR2-R4496C mutant mice from stress-induced VTs. Conclusions : Our results demonstrate that despite severe sarcoplasmic reticulum Ca 2+ leak, PLN-KO suppresses triggered activities and stress-induced VTs in a mouse model of catecholaminergic polymorphic VT. These data suggest that breaking up cell-wide propagating SCWs by enhancing Ca 2+ sequestration represents an effective approach for suppressing Ca 2+ -triggered arrhythmias.

scholarly journals A mouse model of subcortical vascular dementia reflecting degeneration of cerebral white matter and microcirculation

2017 ◽  
Vol 39 (1) ◽  
pp. 44-57 ◽  
Author(s):  
Eek-Sung Lee ◽  
Jin-Hui Yoon ◽  
Jiye Choi ◽  
Faris R Andika ◽  
Taekwan Lee ◽  
...  
Keyword(s):  
Working Memory ◽  
White Matter ◽  
Recognition Memory ◽  
Mouse Model ◽  
Vascular Dementia ◽  
Spatial Working Memory ◽  
Cerebral Hypoperfusion ◽  
Cerebral Microcirculation ◽  
White Matter Damage ◽  
Subcortical Vascular Dementia

Subcortical vascular dementia(SVaD) is associated with white matter damage, lacunar infarction, and degeneration of cerebral microcirculation. Currently available mouse models can mimic only partial aspects of human SVaD features. Here, we combined bilateral common carotid artery stenosis (BCAS) with a hyperlipidaemia model in order to develop a mouse model of SVaD; 10- to 12-week-old apolipoprotein E (ApoE)-deficient or wild-type C57BL/6J mice were subjected to sham operation or chronic cerebral hypoperfusion with BCAS using micro-coils. Behavioural performance (locomotion, spatial working memory, and recognition memory), histopathological findings (white matter damage, microinfarctions, astrogliosis), and cerebral microcirculation (microvascular density and blood–brain barrier (BBB) integrity) were investigated. ApoE-deficient mice subjected to BCAS showed impaired locomotion, spatial working memory, and recognition memory. They also showed white matter damage, multiple microinfarctions, astrogliosis, reduction in microvascular density, and BBB breakdown. The combination of chronic cerebral hypoperfusion and ApoE deficiency induced cognitive decline and cerebrovascular pathology, including white matter damage, multiple microinfarctions, and degeneration of cerebral microcirculation. Together, these features are all compatible with those of patients with SVaD. Thus, the proposed animal model is plausible for investigating SVaD pathophysiology and for application in preclinical drug studies.

NGF Rescues Hippocampal Cholinergic Neuronal Markers, Restores Neurogenesis, and Improves the Spatial Working Memory in a Mouse Model of Huntington's Disease

2013 ◽  
Vol 2 (1) ◽  
pp. 69-82 ◽  
Author(s):  
Hongyu Zhang ◽  
Géraldine H. Petit ◽  
Philip M. Gaughwin ◽  
Christian Hansen ◽  
Srikanth Ranganathan ◽  
...  
Keyword(s):  
Working Memory ◽  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Spatial Working Memory ◽  
Neuronal Markers

The Preliminary Investigation of Multi-Level Working Memory in Predicting Anxiety/Depressive Symptomatology in Childhood/Adolescence

2019 ◽  
Author(s):  
Brian Kavanaugh ◽  
Alexa Fryc ◽  
Simona Temereanca Ibanescu ◽  
Eric Tirrell ◽  
Lindsay Oberman ◽  
...  
Keyword(s):  
Working Memory ◽  
Depressive Symptomatology ◽  
Preliminary Investigation ◽  
Gamma Oscillations ◽  
Composite Score ◽  
Clinical Markers ◽  
Measurement Variability ◽  
Parent Questionnaire ◽  
Gamma Power ◽  
Multi Level

Prior research in working memory (WM) has been hampered by measurement variability and a lack of integration of neural and clinical markers. This study sought to examine whether a multi-level composite of WM with neural, cognitive, and behavioral levels could predict childhood affective symptomatology in seventeen children and adolescents receiving outpatient mental health services. WM-related theta/gamma oscillations at the F3 electrode were measured via electroencephalography (EEG) recording during a spatial WM task. Other measures included a neuropsychological measure of WM, parent questionnaire assessing WM, and self-reported affective symptoms. Gamma power and theta-gamma coupling, but not theta power, predicted high WM demands performance (i.e., 16-19% of variance). Two composite scores were created consisting of gamma power or theta-gamma coupling, clinical WM measure performance, and parent-reported WM symptoms. These multi-level composite score predicted self-reported depressive (22-32% of variance) symptoms, while only the gamma-version of the composite predicted anxious symptoms (39% of variance compared to 12% of variance). A WM composite score consisting of neural, cognitive, and behavioral levels predicted the severity of childhood affective symptomatology. WM, like other EFs, is highly complex and may be most appropriately measured in clinical and research settings with a combination of neural, cognitive, and behavioral measures.

Repetitive Transcranial Magnetic Stimulation Reverses Aβ1–42-induced Dysfunction in Gamma Oscillation during Working Memory

2018 ◽  
Vol 15 (6) ◽  
pp. 570-577 ◽  
Author(s):  
Wenwen Bai ◽  
Tiaotiao Liu ◽  
Mengmeng Dou ◽  
Mi Xia ◽  
Jun Lu ◽  
...  
Keyword(s):  
Working Memory ◽  
Transcranial Magnetic Stimulation ◽  
Magnetic Stimulation ◽  
Repetitive Transcranial Magnetic Stimulation ◽  
Memory Task ◽  
Amyloid Β ◽  
Gamma Oscillations ◽  
Causative Factor ◽  
Gamma Oscillation ◽  
Amyloid Β Peptide

Background: Alzheimer's disease (AD) is a neurodegenerative disease that gradually induces cognitive deficits in the elderly and working memory impairment is typically observed in AD. Amyloid-β peptide (Aβ) is a causative factor for the cognitive impairments in AD. Gamma oscillations have been recognized to play important roles in various cognitive functions including working memory. Previous study reported that Aβ induces gamma oscillation dysfunction in working memory. Objective: Although repetitive transcranial magnetic stimulation (rTMS) represents a technique for noninvasive stimulation to induce cortical activity and excitability changes and has been accepted for increasing brain excitability and regulating cognitive behavior, the question whether rTMS can reserve the Aβ-induced gamma oscillation dysfunction during working memory remains unclear. The present study aims to investigate the effect of rTMS to the Aβ-induced gamma oscillation dysfunction during working memory. Method: The present study investigates the rTMS-modulated gamma oscillation in Aβ1-42-induced memory deficit. Adult SD rats were divided into four groups: Aβ, Con, Aβ+rTMS and Con+rTMS. 16-channel local field potentials (LFPs) were recorded from rat medial prefrontal cortex while the rats performed a Y-maze working memory task. Gamma oscillation among LFPs was measured by coherence. Results: The results show that rTMS improved the behavior performance and enhanced gamma oscillation for the Aβ-injected subjects. Conclusion: These results indicate that rTMS may reserve the Aβ-induced dysfunction in gamma oscillation during working memory and thus result in potential benefits for working memory.

scholarly journals Hirano body expression impairs spatial working memory in a novel mouse model

2014 ◽  
Vol 2 (1) ◽  
Author(s):  
Matthew Furgerson ◽  
Jason K. Clark ◽  
Jonathon D. Crystal ◽  
John J. Wagner ◽  
Marcus Fechheimer ◽  
...  
Keyword(s):  
Working Memory ◽  
Mouse Model ◽  
Spatial Working Memory ◽  
Hirano Body ◽  
Body Expression

scholarly journals Tracking the Contents of Spatial Working Memory during an Acute Bout of Aerobic Exercise

2021 ◽  
pp. 1-16
Author(s):  
Jordan Garrett ◽  
Tom Bullock ◽  
Barry Giesbrecht
Keyword(s):  
Working Memory ◽  
Aerobic Exercise ◽  
Neural Coding ◽  
Spatial Working Memory ◽  
Brain Activity ◽  
Stimulus Presentation ◽  
Visual Responses ◽  
Acute Bout ◽  
Exercise Condition ◽  
Sensory Evoked

Abstract Recent studies have reported enhanced visual responses during acute bouts of physical exercise, suggesting that sensory systems may become more sensitive during active exploration of the environment. This raises the possibility that exercise may also modulate brain activity associated with other cognitive functions, like visual working memory, that rely on patterns of activity that persist beyond the initial sensory evoked response. Here, we investigated whether the neural coding of an object location held in memory is modulated by an acute bout of aerobic exercise. Participants performed a spatial change detection task while seated on a stationary bike at rest and during low-intensity cycling (∼50 watts/50 RPM). Brain activity was measured with EEG. An inverted encoding modeling technique was employed to estimate location-selective channel response functions from topographical patterns of alpha-band (8–12 Hz) activity. There was strong evidence of robust spatially selective responses during stimulus presentation and retention periods both at rest and during exercise. During retention, the spatial selectivity of these responses decreased in the exercise condition relative to rest. A temporal generalization analysis indicated that models trained on one time period could be used to reconstruct the remembered locations at other time periods, providing evidence that a unitary code supports memory during both conditions. However, generalization was degraded during exercise. Together, these results demonstrate that it is possible to reconstruct the contents of working memory at rest and during exercise, but that exercise can result in degraded responses, which contrasts with the enhancements observed in early sensory processing.

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