Synaptic plasticity and spatial working memory are impaired in the CD mouse model of Williams-Beuren syndrome

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.

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Synergy between vesicular and non-vesicular gliotransmission regulates synaptic plasticity and working memory

10.1101/2021.03.25.437028 ◽

2021 ◽

Author(s):

Ulyana Lalo ◽

Seyed Rasooli-Nejad ◽

Alexander Bogdanov ◽

Lorenzo More ◽

Wuhyun Koh ◽

...

Keyword(s):

Working Memory ◽

Synaptic Plasticity ◽

Small Molecule ◽

Environmental Enrichment ◽

Pyramidal Neurons ◽

Active Element ◽

Spatial Working Memory ◽

Phasic Response ◽

Cortical Astrocytes

Astrocytes are an active element of brain signalling, capable of release of small molecule gliotransmitters by vesicular and channel-mediated mechanisms. However, specific physiological roles of astroglial exocytosis of glutamate and D-Serine remain controversial. Our data demonstrate that cortical astrocytes can release glutamate and D-Serine by combination of SNARE-dependent exocytosis and non-vesicular mechanisms dependent on TREK-1 and Best1 channels. Astrocyte-derived glutamate and D-serine elicited complex multicomponent phasic response in neocortical pyramidal neurons, which is mediated by extra-synaptic GluN2B receptors. Impairment of either pathway of gliotransmission (in the TREK1 KO, Best-1 KO or dnSNARE mice) strongly affected the NMDAR-dependent long-term synaptic plasticity in the hippocampus and neocortex. Moreover, impairment of astroglial exocytosis in dnSNARE mice led to the deficit in the spatial working memory which was rescued by environmental enrichment. We conclude that synergism between vesicular and non-vesicular gliotransmission is crucial for astrocyte-neuron communication and astroglia-driven regulation of synaptic plasticity and memory.

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Autophagy is required for human umbilical cord mesenchymal stem cells to improve spatial working memory in APP/PS1 transgenic mouse model

Stem Cell Research & Therapy ◽

10.1186/s13287-017-0756-2 ◽

2018 ◽

Vol 9 (1) ◽

Cited By ~ 11

Author(s):

Wen Li ◽

Kai Li ◽

Jing Gao ◽

Zhuo Yang

Keyword(s):

Stem Cells ◽

Working Memory ◽

Mesenchymal Stem Cells ◽

Mouse Model ◽

Transgenic Mouse ◽

Umbilical Cord ◽

Spatial Working Memory ◽

Transgenic Mouse Model ◽

Human Umbilical Cord

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Alterations in synaptic plasticity coincide with deficits in spatial working memory in presymptomatic 3xTg-AD mice

Neurobiology of Learning and Memory ◽

10.1016/j.nlm.2015.09.003 ◽

2015 ◽

Vol 125 ◽

pp. 152-162 ◽

Cited By ~ 38

Author(s):

Jason K. Clark ◽

Matthew Furgerson ◽

Jonathon D. Crystal ◽

Marcus Fechheimer ◽

Ruth Furukawa ◽

...

Keyword(s):

Working Memory ◽

Synaptic Plasticity ◽

Spatial Working Memory

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x17736963 ◽

2017 ◽

Vol 39 (1) ◽

pp. 44-57 ◽

Cited By ~ 9

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.

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The Effects of Intraoperative Hypothermia on Postoperative Cognitive Function in the Rat Hippocampus and Its Possible Mechanisms

Brain Sciences ◽

10.3390/brainsci12010096 ◽

2022 ◽

Vol 12 (1) ◽

pp. 96

Author(s):

Guangyan Xu ◽

Tianjia Li ◽

Yuguang Huang

Keyword(s):

Working Memory ◽

Synaptic Plasticity ◽

Cognitive Function ◽

Learning And Memory ◽

Spatial Learning ◽

Hippocampal Neurons ◽

Spatial Working Memory ◽

Postoperative Cognitive Dysfunction ◽

Spatial Learning And Memory ◽

Intraoperative Hypothermia

Intraoperative hypothermia is a common complication during operations and is associated with several adverse events. Postoperative cognitive dysfunction (POCD) and its adverse consequences have drawn increasing attention in recent years. There are currently no relevant studies investigating the correlation between intraoperative hypothermia and POCD. The aim of this study was to assess the effects of intraoperative hypothermia on postoperative cognitive function in rats undergoing exploratory laparotomies and to investigate the possible related mechanisms. We used the Y-maze and Morris Water Maze (MWM) tests to assess the rats’ postoperative spatial working memory, spatial learning, and memory. The morphological changes in hippocampal neurons were examined by haematoxylin-eosin (HE) staining and hippocampal synaptic plasticity-related protein expression. Activity-regulated cytoskeletal-associated protein (Arc), cyclic adenosine monophosphate-response element-binding protein (CREB), S133-phosphorylated CREB (p-CREB [S133]), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor 1 (AMPAR1), and S831-phosphorylated AMPAR1 (p-AMPAR1 [S831]) were evaluated by Western blotting. Our results suggest a correlation between intraoperative hypothermia and POCD in rats and that intraoperative hypothermia may lead to POCD regarding impairments in spatial working memory, spatial learning, and memory. POCD induced by intraoperative hypothermia might be due to hippocampal neurons damage and decreased expression of synaptic plasticity-related proteins Arc, p-CREB (S133), and p-AMPAR1 (S831).

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