scholarly journals Amyloid Beta-Mediated Changes in Synaptic Function and Spine Number of Neocortical Neurons Depend on NMDA Receptors

2021 ◽  
Vol 22 (12) ◽  
pp. 6298
Author(s):  
Michaela K. Back ◽  
Sonia Ruggieri ◽  
Eric Jacobi ◽  
Jakob von Engelhardt
Keyword(s):  
Nmda Receptors ◽  
Amyloid Beta ◽  
Expression Profiles ◽  
Pyramidal Cells ◽  
Brain Regions ◽  
Synaptic Function ◽  
Neocortical Neurons ◽  
5Xfad Mice ◽  
Spine Number

Onset and progression of Alzheimer’s disease (AD) pathophysiology differs between brain regions. The neocortex, for example, is a brain region that is affected very early during AD. NMDA receptors (NMDARs) are involved in mediating amyloid beta (Aβ) toxicity. NMDAR expression, on the other hand, can be affected by Aβ. We tested whether the high vulnerability of neocortical neurons for Aβ-toxicity may result from specific NMDAR expression profiles or from a particular regulation of NMDAR expression by Aβ. Electrophysiological analyses suggested that pyramidal cells of 6-months-old wildtype mice express mostly GluN1/GluN2A NMDARs. While synaptic NMDAR-mediated currents are unaltered in 5xFAD mice, extrasynaptic NMDARs seem to contain GluN1/GluN2A and GluN1/GluN2A/GluN2B. We used conditional GluN1 and GluN2B knockout mice to investigate whether NMDARs contribute to Aβ-toxicity. Spine number was decreased in pyramidal cells of 5xFAD mice and increased in neurons with 3-week virus-mediated Aβ-overexpression. NMDARs were required for both Aβ-mediated changes in spine number and functional synapses. Thus, our study gives novel insights into the Aβ-mediated regulation of NMDAR expression and the role of NMDARs in Aβ pathophysiology in the somatosensory cortex.

scholarly journals Presynaptic NMDA receptors facilitate short-term plasticity and BDNF release at hippocampal mossy fiber synapses

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Pablo J Lituma ◽  
Hyung-Bae Kwon ◽  
Karina Alviña ◽  
Rafael Luján ◽  
Pablo E Castillo
Keyword(s):  
Nmda Receptors ◽  
Information Transfer ◽  
Mossy Fiber ◽  
Pyramidal Cells ◽  
Synaptic Function ◽  
Fine Tuning ◽  
Short Term ◽  
Dentate Granule Cell ◽  
Presynaptic Calcium ◽  
Presynaptic Nmda Receptors

Neurotransmitter release is a highly controlled process by which synapses can critically regulate information transfer within neural circuits. While presynaptic receptors –typically activated by neurotransmitters and modulated by neuromodulators– provide a powerful way of fine-tuning synaptic function, their contribution to activity-dependent changes in transmitter release remains poorly understood. Here, we report that presynaptic NMDA receptors (preNMDARs) at mossy fiber boutons in the rodent hippocampus can be activated by physiologically relevant patterns of activity and selectively enhance short-term synaptic plasticity at mossy fiber inputs onto CA3 pyramidal cells and mossy cells, but not onto inhibitory interneurons. Moreover, preNMDARs facilitate brain-derived neurotrophic factor (BDNF) release and contribute to presynaptic calcium rise. Taken together, our results indicate that by increasing presynaptic calcium, preNMDARs fine tune mossy fiber neurotransmission and can control information transfer during dentate granule cell burst activity that normally occur in vivo.

scholarly journals Cilium Expression Score Predicts Glioma Survival

2021 ◽  
Vol 12 ◽  
Author(s):  
Srinivas Rajagopalan ◽  
Amartya Singh ◽  
Hossein Khiabanian
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Brain Regions ◽  
Poor Survival ◽  
Aggressive Tumors ◽  
Regulated Gene Expression ◽  
Upregulated Genes ◽  
Expression Score

The accurate classification, prognostication, and treatment of gliomas has been hindered by an existing cellular, genomic, and transcriptomic heterogeneity within individual tumors and their microenvironments. Traditional clustering is limited in its ability to distinguish heterogeneity in gliomas because the clusters are required to be exclusive and exhaustive. In contrast, biclustering can identify groups of co-regulated genes with respect to a subset of samples and vice versa. In this study, we analyzed 1,798 normal and tumor brain samples using an unsupervised biclustering approach. We identified co-regulated gene expression profiles that were linked to proximally located brain regions and detected upregulated genes in subsets of gliomas, associated with their histologic grade and clinical outcome. In particular, we present a cilium-associated signature that when upregulated in tumors is predictive of poor survival. We also introduce a risk score based on expression of 12 cilium-associated genes which is reproducibly informative of survival independent of other prognostic biomarkers. These results highlight the role of cilia in development and progression of gliomas and suggest potential therapeutic vulnerabilities for these highly aggressive tumors.

scholarly journals Presynaptic NMDA receptors facilitate short-term plasticity and BDNF release at hippocampal mossy fiber synapses

2021 ◽  
Author(s):  
Pablo J. Lituma ◽  
Hyung-Bae Kwon ◽  
Rafael Lujan ◽  
Pablo E. Castillo
Keyword(s):  
Nmda Receptors ◽  
Information Transfer ◽  
Mossy Fiber ◽  
Pyramidal Cells ◽  
Synaptic Function ◽  
Fine Tuning ◽  
Short Term ◽  
Dentate Granule Cell ◽  
Presynaptic Calcium ◽  
Presynaptic Nmda Receptors

AbstractNeurotransmitter release is a highly controlled process by which synapses can critically regulate information transfer within neural circuits. While presynaptic receptors –typically activated by neurotransmitters and modulated by neuromodulators– provide a powerful way of fine tuning synaptic function, their contribution to activity-dependent changes in transmitter release remains poorly understood. Here, we report that presynaptic NMDA receptors (preNMDARs) at hippocampal mossy fiber boutons can be activated by physiologically relevant patterns of activity and selectively enhance short-term synaptic plasticity at mossy fiber inputs onto CA3 pyramidal cells and mossy cells, but not onto inhibitory interneurons. Moreover, preNMDARs facilitate brain-derived neurotrophic factor (BDNF) release and contribute to presynaptic calcium rise. Taken together, our results indicate that preNMDARs, by increasing presynaptic calcium, fine tune mossy fiber neurotransmission and can control information transfer during dentate granule cell burst activity that normally occur in vivo.

scholarly journals Postnatal BDNF Expression Profiles in Prefrontal Cortex and Hippocampus of a Rat Schizophrenia Model Induced by MK-801 Administration

2010 ◽  
Vol 2010 ◽  
pp. 1-5 ◽  
Author(s):  
Chunmei Guo ◽  
Yang Yang ◽  
Yun'ai Su ◽  
Tianmei Si
Keyword(s):  
Prefrontal Cortex ◽  
Nmda Receptors ◽  
Expression Profiles ◽  
Current Model ◽  
Brain Regions ◽  
Nmda Receptor Antagonist ◽  
Sprague Dawley ◽  
Bdnf Expression ◽  
Mk 801 ◽  
Protein Levels

Neonatal blockade of N-methyl-D-aspartic acid (NMDA) receptors represents one of experimental animal models for schizophrenia. This study is to investigate the long-term brain-derived neurotrophic factor (BDNF) expression profiles in different regions and correlation with “schizophrenia-like” behaviors in the adolescence and adult of this rat model. The NMDA receptor antagonist MK801 was administered to female Sprague-Dawley rats on postnatal days (PND) 5 through 14. Open-field test was performed on PND 42, and PND 77 to examine the validity of the current model. BDNF protein levels in hippocampus and prefrontal cortex (PFC) were analyzed on PND 15, PND 42, and PND 77. Results showed that neonatal challenge with MK-801 persistently elevated locomotor activity as well as BDNF expression; the alterations in BDNF expression varied at different developing stages and among brain regions. However, these findings provide neurochemical evidence that the blockade of NMDA receptors during brain development results in long-lasting alterations in BDNF expression and might contribute to neurobehavioral pathology of the present animal model for schizophrenia. Further study in the mechanisms and roles of the BDNF may lead to better understanding of the pathophysiology of schizophrenia.

scholarly journals Potassium Channels and Their Potential Roles in Substance Use Disorders

2021 ◽  
Vol 22 (3) ◽  
pp. 1249
Author(s):  
Michael T. McCoy ◽  
Subramaniam Jayanthi ◽  
Jean Lud Cadet
Keyword(s):  
Substance Use ◽  
Potassium Channels ◽  
Potassium Channel ◽  
Substance Use Disorders ◽  
Expression Profiles ◽  
Brain Regions ◽  
Firing Frequency ◽  
Therapeutic Interventions ◽  
Channel Expression

Substance use disorders (SUDs) are ubiquitous throughout the world. However, much remains to be done to develop pharmacotherapies that are very efficacious because the focus has been mostly on using dopaminergic agents or opioid agonists. Herein we discuss the potential of using potassium channel activators in SUD treatment because evidence has accumulated to support a role of these channels in the effects of rewarding drugs. Potassium channels regulate neuronal action potential via effects on threshold, burst firing, and firing frequency. They are located in brain regions identified as important for the behavioral responses to rewarding drugs. In addition, their expression profiles are influenced by administration of rewarding substances. Genetic studies have also implicated variants in genes that encode potassium channels. Importantly, administration of potassium agonists have been shown to reduce alcohol intake and to augment the behavioral effects of opioid drugs. Potassium channel expression is also increased in animals with reduced intake of methamphetamine. Together, these results support the idea of further investing in studies that focus on elucidating the role of potassium channels as targets for therapeutic interventions against SUDs.

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