scholarly journals Astrocyte dysfunction increases cortical dendritic excitability and promotes cranial pain in familial migraine

2020 ◽  
Vol 6 (23) ◽  
pp. eaaz1584 ◽  
Author(s):  
Jennifer Romanos ◽  
Dietmar Benke ◽  
Daniela Pietrobon ◽  
Hanns Ulrich Zeilhofer ◽  
Mirko Santello
Keyword(s):  
Mouse Model ◽  
Pyramidal Neurons ◽  
Glutamate Uptake ◽  
Cingulate Cortex ◽  
Familial Hemiplegic Migraine ◽  
Strong Impact ◽  
Two Photon Microscopy ◽  
Genetic Mouse Model ◽  
Cortical Physiology ◽  
And Behavior

Astrocytes are essential contributors to neuronal function. As a consequence, disturbed astrocyte-neuron interactions are involved in the pathophysiology of several neurological disorders, with a strong impact on brain circuits and behavior. Here, we describe altered cortical physiology in a genetic mouse model of familial hemiplegic migraine type 2 (FHM2), with reduced expression of astrocytic Na+,K+-ATPases. We used whole-cell electrophysiology, two-photon microscopy, and astrocyte gene rescue to demonstrate that an impairment in astrocytic glutamate uptake promotes NMDA spike generation in dendrites of cingulate cortex pyramidal neurons and enhances output firing of these neurons. Astrocyte compensation of the defective ATPase in the cingulate cortex rescued glutamate uptake, prevented abnormal NMDA spikes, and reduced sensitivity to cranial pain triggers. Together, our results demonstrate that impaired astrocyte function alters neuronal activity in the cingulate cortex and facilitates migraine-like cranial pain states in a mouse model of migraine.

Calcium dysregulation and compensation in cortical pyramidal neurons of the R6/2 mouse model of Huntington’s disease

2021 ◽  
Vol 126 (4) ◽  
pp. 1159-1171
Author(s):  
Katerina D. Oikonomou ◽  
Elissa J. Donzis ◽  
Minh T. N. Bui ◽  
Carlos Cepeda ◽  
Michael S. Levine
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Pyramidal Neurons ◽  
Calcium Influx ◽  
Calcium Transient ◽  
Two Photon Microscopy ◽  
Decay Times ◽  
Cortical Pyramidal Neurons ◽  
Receptor Blockers

We used two-photon microscopy to examine calcium influx induced by action potentials in cortical pyramidal neurons from a mouse model of Huntington’s disease (HD), the R6/2. The amplitude of somatic calcium transients was reduced in R6/2 mice compared with controls. This reduction was compensated by increased decay times, which could lead to reduced calcium buffering capacity. L-type calcium channel and ryanodine receptor blockers reduced calcium transient area in HD neurons, suggesting new therapeutic avenues.

scholarly journals Genetic disruption of ankyrin-G in adult mouse forebrain causes cortical synapse alteration and behavior reminiscent of bipolar disorder

2017 ◽  
Vol 114 (39) ◽  
pp. 10479-10484 ◽  
Author(s):  
Shanshan Zhu ◽  
Zachary A. Cordner ◽  
Jiali Xiong ◽  
Chi-Tso Chiu ◽  
Arabiye Artola ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Mouse Model ◽  
Pyramidal Neurons ◽  
Association Studies ◽  
Behavioral Changes ◽  
Genome Wide Association Studies ◽  
Ankyrin G ◽  
Genome Wide ◽  
Cortical Pyramidal Neurons ◽  
And Behavior

Genome-wide association studies have implicated the ANK3 locus in bipolar disorder, a major human psychotic illness. ANK3 encodes ankyrin-G, which organizes the neuronal axon initial segment (AIS). We generated a mouse model with conditional disruption of ANK3 in pyramidal neurons of the adult forebrain (Ank-G cKO). This resulted in the expected loss of pyramidal neuron AIS voltage-gated sodium and potassium channels. There was also dramatic loss of markers of afferent GABAergic cartridge synapses, resembling the cortical microcircuitry changes in brains from psychotic patients, and suggesting disinhibition. Expression of c-fos was increased in cortical pyramidal neurons, consistent with increased neuronal activity due to disinhibition. The mice showed robust behavioral phenotypes reminiscent of aspects of human mania, ameliorated by antimania drugs lithium and valproate. Repeated social defeat stress resulted in repeated episodes of dramatic behavioral changes from hyperactivity to “depression-like” behavior, suggestive of some aspects of human bipolar disorder. Overall, we suggest that this Ank-G cKO mouse model recapitulates some of the core features of human bipolar disorder and indicates that cortical microcircuitry alterations during adulthood may be involved in pathogenesis. The model may be useful for studying disease pathophysiology and for developing experimental therapeutics.

scholarly journals Neonatal oxytocin impacts hippocampal network development and restores adult social memory in a mouse model of autism

2020 ◽  
Author(s):  
Alessandra Bertoni ◽  
Fabienne Schaller ◽  
Roman Tyzio ◽  
Stephane Gaillard ◽  
Francesca Santini ◽  
...  
Keyword(s):  
Mouse Model ◽  
Neurodevelopmental Disorders ◽  
Hippocampal Neurons ◽  
Pyramidal Neurons ◽  
Social Memory ◽  
Strong Impact ◽  
Adult Mice ◽  
Ca3 Neurons ◽  
The Brain ◽  
Deficient Mice

AbstractPrader-Willi (PW) and Schaaf-Yang (SY) syndromes are genetic neurodevelopmental disorders involving MAGEL2 gene. Magel2-deficient mice mimic the symptoms common to both diseases, in particular autistic-like symptoms. Importantly, peripheral administration of oxytocin during infancy cures social deficiency of Magel2-KO mice beyond treatment into adulthood. However, neurobiological alterations related to oxytocin-signaling and responsible for social deficits are poorly explored in mouse models of autism, including Magel2-deficient mice. Moreover, the mechanisms by which neonatal oxytocin-administration improves social behavior remain unknown. Here, by studying Magel2-KO mice, we aim to decipher the mechanisms underlying the PWS/SYS social alterations and their rescue by oxytocin.Hippocampal neurons in Dentate Gyrus and CA2/CA3 regions are associated with social memory engrams involving the oxytocin-system. We have shown that Magel2 and oxytocin-receptor are specifically co-expressed in those neurons during development. Then, in Magel2-deficient adult mice, we showed a deficit of social memory and revealed an increase of spontaneous inhibitory activity of pyramidal neurons, a higher number of somatostatin-positive interneurons and an increase in the number of oxytocin-receptors. We also showed a delay in the GABAergic developmental sequence in CA3 neurons associated with biochemical changes in potassium-chloride cotransporter KCC2. Importantly, we demonstrated a strong impact of neonatal oxytocin administration, rescuing all these neuronal alterations.This study elucidates the mechanisms by which peripheral oxytocin-administration in neonates affects the brain social circuitry. While clinical trials are ongoing, we are demonstrating the therapeutic value of administrating oxytocin in newborns to treat patients with Prader-Willi and Schaaf-Yang syndromes and possibly other neurodevelopmental disorders related to autism.Single sentence summaryThis study reveals how peripheral administration of oxytocin in newborns treats alterations in the brain social circuits described in a mouse model of autism.

1734-P: High Dietary Fat Intake Exacerbates Insulin Resistance in a Type 2 Diabetes Genetic Mouse Model

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 1734-P
Author(s):  
AUSTIN REILLY ◽  
SHIJUN YAN ◽  
ALEXA J. LONCHARICH ◽  
HONGXIA REN
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Mouse Model ◽  
Dietary Fat ◽  
Fat Intake ◽  
Dietary Fat Intake ◽  
Genetic Mouse Model

scholarly journals Control of impulsivity by Gi-protein signalling in layer-5 pyramidal neurons of the anterior cingulate cortex

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Bastiaan van der Veen ◽  
Sampath K. T. Kapanaiah ◽  
Kasyoka Kilonzo ◽  
Peter Steele-Perkins ◽  
Martin M. Jendryka ◽  
...  
Keyword(s):  
Gene Expression ◽  
Anterior Cingulate Cortex ◽  
Expression Analysis ◽  
Gene Expression Analysis ◽  
Pyramidal Neurons ◽  
Treatment Options ◽  
Pyramidal Cells ◽  
Cingulate Cortex ◽  
Cell Types ◽  
Anterior Cingulate

AbstractPathological impulsivity is a debilitating symptom of multiple psychiatric diseases with few effective treatment options. To identify druggable receptors with anti-impulsive action we developed a systematic target discovery approach combining behavioural chemogenetics and gene expression analysis. Spatially restricted inhibition of three subdivisions of the prefrontal cortex of mice revealed that the anterior cingulate cortex (ACC) regulates premature responding, a form of motor impulsivity. Probing three G-protein cascades with designer receptors, we found that the activation of Gi-signalling in layer-5 pyramidal cells (L5-PCs) of the ACC strongly, reproducibly, and selectively decreased challenge-induced impulsivity. Differential gene expression analysis across murine ACC cell-types and 402 GPCRs revealed that - among Gi-coupled receptor-encoding genes - Grm2 is the most selectively expressed in L5-PCs while alternative targets were scarce. Validating our approach, we confirmed that mGluR2 activation reduced premature responding. These results suggest Gi-coupled receptors in ACC L5-PCs as therapeutic targets for impulse control disorders.

scholarly journals Pra-C exerts analgesic effect through inhibiting microglial activation in anterior cingulate cortex in complete Freund’s adjuvant-induced mouse model

2021 ◽  
Vol 17 ◽  
pp. 174480692199093
Author(s):  
Dan-jie Su ◽  
Long-fei Li ◽  
Sai-ying Wang ◽  
Qi Yang ◽  
Yu-jing Wu ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Mouse Model ◽  
Anterior Cingulate Cortex ◽  
Analgesic Effect ◽  
Microglial Activation ◽  
Cingulate Cortex ◽  
Anterior Cingulate ◽  
Freund’S Adjuvant ◽  
Complete Freund's Adjuvant ◽  
Freund's Adjuvant

Chronic pain is highly prevalent worldwide and severely affects daily lives of patients and family members. Praeruptorin C (Pra-C) is a main active ingredient derived from Peucedanum praeruptorum Dunn, traditionally used as antibechic, anti-bronchitis and anti-hypertension drug. Here, we evaluated the effects of Pra-C in a chronic inflammatory pain mouse model induced by complete Freund’s adjuvant (CFA) injection. Pra-C (3 mg/kg) treatment for just 3 days after CFA challenge relieved CFA-induced mechanical allodynia and hindpaw edema in mice. In the anterior cingulate cortex (ACC), Pra-C treatment inhibited microglia activation and reduced levels of proinflammatory cytokines, TNF-α and IL-1β, and suppressed upregulation of glutamate receptors caused by CFA injection. In addition, Pra-C attenuated neuronal hyperexcitability in ACC of CFA-injected mice. In vitro studies confirmed the analgesic effect of Pra-C was due to its inhibitory ability on microglial activation. In conclusion, Pra-C administration had a certain effect on relieving chronic pain by inhibiting microglial activation, attenuating proinflammatory cytokine releasing and regulating excitatory synaptic proteins in the ACC of the CFA-injected mice.

scholarly journals Carrot Supplementation Improves Blood Pressure and Reduces Aortic Root Lesions in an Atherosclerosis-Prone Genetic Mouse Model

Nutrients ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 1181
Author(s):  
Raffaella Soleti ◽  
Marine Coué ◽  
Charlotte Trenteseaux ◽  
Gregory Hilairet ◽  
Lionel Fizanne ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Mouse Model ◽  
Aortic Root ◽  
De Novo ◽  
Body Weight Gain ◽  
Density Lipoprotein ◽  
De Novo Lipogenesis ◽  
Hemodynamic Parameters ◽  
Cellular Models ◽  
Genetic Mouse Model

Epidemiological studies have shown that carrot consumption may be associated with a lower risk of developing several metabolic dysfunctions. Our group previously determined that the Bolero (Bo) carrot variety exhibited vascular and hepatic tropism using cellular models of cardiometabolic diseases. The present study evaluated the potential metabolic and cardiovascular protective effect of Bo, grown under two conditions (standard and biotic stress conditions (BoBS)), in apolipoprotein E-knockout (ApoE−/−) mice fed with high fat diet (HFD). Effects on metabolic/hemodynamic parameters and on atherosclerotic lesions have been assessed. Both Bo and BoBS decreased plasma triglyceride and expression levels of genes implicated in hepatic de novo lipogenesis and lipid oxidation. BoBS supplementation decreased body weight gain, secretion of very-low-density lipoprotein, and increased cecal propionate content. Interestingly, Bo and BoBS supplementation improved hemodynamic parameters by decreasing systolic, diastolic, and mean blood pressure. Moreover, Bo improved cardiac output. Finally, Bo and BoBS substantially reduced the aortic root lesion area. These results showed that Bo and BoBS enriched diets corrected most of the metabolic and cardiovascular disorders in an atherosclerosis-prone genetic mouse model and may therefore represent an interesting nutritional approach for the prevention of cardiovascular diseases.

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