scholarly journals Electrophysiological changes precede morphological changes to frontal cortical pyramidal neurons in the rTg4510 mouse model of progressive tauopathy

2012 ◽  
Vol 124 (6) ◽  
pp. 777-795 ◽  
Author(s):  
Johanna L. Crimins ◽  
Anne B. Rocher ◽  
Jennifer I. Luebke
Keyword(s):  
Mouse Model ◽  
Pyramidal Neurons ◽  
Morphological Changes ◽  
Rtg4510 Mouse ◽  
Cortical Pyramidal Neurons

Ectopic HCN4 expression drives mTOR-dependent epilepsy in mice

2020 ◽  
Vol 12 (570) ◽  
pp. eabc1492
Author(s):  
Lawrence S. Hsieh ◽  
John H. Wen ◽  
Lena H. Nguyen ◽  
Longbo Zhang ◽  
Stephanie A. Getz ◽  
...  
Keyword(s):  
Mouse Model ◽  
Pyramidal Neurons ◽  
Focal Cortical Dysplasia ◽  
Repetitive Firing ◽  
Intracellular Camp ◽  
Main Role ◽  
Channel Activity ◽  
Mechanistic Target Of Rapamycin ◽  
Cortical Pyramidal Neurons ◽  
Causative Link

The causative link between focal cortical malformations (FCMs) and epilepsy is well accepted, especially among patients with focal cortical dysplasia type II (FCDII) and tuberous sclerosis complex (TSC). However, the mechanisms underlying seizures remain unclear. Using a mouse model of TSC- and FCDII-associated FCM, we showed that FCM neurons were responsible for seizure activity via their unexpected abnormal expression of the hyperpolarization-activated cyclic nucleotide–gated potassium channel isoform 4 (HCN4), which is normally not present in cortical pyramidal neurons after birth. Increasing intracellular cAMP concentrations, which preferentially affects HCN4 gating relative to the other isoforms, drove repetitive firing of FCM neurons but not control pyramidal neurons. Ectopic HCN4 expression was dependent on the mechanistic target of rapamycin (mTOR), preceded the onset of seizures, and was also found in diseased neurons in tissue resected from patients with TSC and FCDII. Last, blocking HCN4 channel activity in FCM neurons prevented epilepsy in the mouse model. These findings suggest that HCN4 play a main role in seizure and identify a cAMP-dependent seizure mechanism in TSC and FCDII. Furthermore, the unique expression of HCN4 exclusively in FCM neurons suggests that gene therapy targeting HCN4 might be effective in reducing seizures in FCDII or TSC.

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.

Altered Function of Hippocampal CA1 Pyramidal Neurons in the rTg4510 Mouse Model of Tauopathy

2014 ◽  
Vol 40 (2) ◽  
pp. 429-442 ◽  
Author(s):  
Nils Ole Dalby ◽  
Christiane Volbracht ◽  
Lone Helboe ◽  
Peter Hjørringaard Larsen ◽  
Henrik Sindal Jensen ◽  
...  
Keyword(s):  
Mouse Model ◽  
Pyramidal Neurons ◽  
Rtg4510 Mouse ◽  
Ca1 Pyramidal Neurons ◽  
Hippocampal Ca1

scholarly journals Altered excitatory and inhibitory inputs to striatal medium-sized spiny neurons and cortical pyramidal neurons in the Q175 mouse model of Huntington's disease

2015 ◽  
Vol 113 (7) ◽  
pp. 2953-2966 ◽  
Author(s):  
Tim Indersmitten ◽  
Conny H. Tran ◽  
Carlos Cepeda ◽  
Michael S. Levine
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Primary Motor Cortex ◽  
Pyramidal Neurons ◽  
Membrane Properties ◽  
Postsynaptic Currents ◽  
Spiny Neurons ◽  
Cortical Pyramidal Neurons ◽  
Intrinsic Membrane Properties

The Q175 knockin mouse model of Huntington's disease (HD) carries a CAG trinucleotide expansion of the human mutant huntingtin allele in its native mouse genomic context and recapitulates the genotype more closely than transgenic models. In this study we examined the progression of changes in intrinsic membrane properties and excitatory and inhibitory synaptic transmission, using whole cell patch-clamp recordings of medium-sized spiny neurons (MSNs) in the dorsolateral striatum and cortical pyramidal neurons (CPNs) in layers 2/3 of the primary motor cortex in brain slices from heterozygous (Q175+/−) and homozygous (Q175+/+) mice. Input resistance in MSNs from Q175+/+ and Q175+/− mice was significantly increased compared with wild-type (WT) littermates beginning at 2 mo. Furthermore, the frequency of spontaneous and miniature excitatory postsynaptic currents (EPSCs) was significantly reduced in MSNs from Q175+/+ and Q175+/− mice compared with WTs beginning at 7 mo. In contrast, the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) and IPSC-to-EPSC ratios were increased in MSNs from Q175+/+ mice beginning at 2 mo. Morphologically, significant decreases in spine density of MSNs from Q175+/− and Q175+/+ mice occurred at 7 and 12 mo. In CPNs, sIPSC frequencies and IPSC-to-EPSC ratios were significantly increased in Q175+/− mice compared with WTs at 12 mo. There were no changes in intrinsic membrane properties or morphology. In summary, we show a number of alterations in electrophysiological and morphological properties of MSNs in Q175 mice that are similar to other HD mouse models. However, unlike other models, CPN inhibitory activity is increased in Q175+/− mice, indicating reduced cortical excitability.

scholarly journals Phospho-Tau Accumulation and Structural Alterations of the Golgi Apparatus of Cortical Pyramidal Neurons in the P301S Tauopathy Mouse Model

2017 ◽  
Vol 60 (2) ◽  
pp. 651-661 ◽  
Author(s):  
Alejandro Antón-Fernández ◽  
Jesús Merchán-Rubira ◽  
Jesús Avila ◽  
Félix Hernández ◽  
Javier DeFelipe ◽  
...  
Keyword(s):  
Golgi Apparatus ◽  
Mouse Model ◽  
Pyramidal Neurons ◽  
Structural Alterations ◽  
Cortical Pyramidal Neurons

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 Morphological changes of cortical pyramidal neurons in hepatic encephalopathy

2014 ◽  
Vol 15 (1) ◽  
Author(s):  
Jeng-Rung Chen ◽  
Bing-Ning Wang ◽  
Guo-Fang Tseng ◽  
Yueh-Jan Wang ◽  
Yong-San Huang ◽  
...  
Keyword(s):  
Hepatic Encephalopathy ◽  
Pyramidal Neurons ◽  
Morphological Changes ◽  
Cortical Pyramidal Neurons

scholarly journals Reversal of dendritic phenotypes in 16p11.2 microduplication mouse model neurons by pharmacological targeting of a network hub

2016 ◽  
Vol 113 (30) ◽  
pp. 8520-8525 ◽  
Author(s):  
Katherine D. Blizinsky ◽  
Blanca Diaz-Castro ◽  
Marc P. Forrest ◽  
Britta Schürmann ◽  
Anthony P. Bach ◽  
...  
Keyword(s):  
Mental Disorders ◽  
Mouse Model ◽  
Gene Networks ◽  
Pyramidal Neurons ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Driver Gene ◽  
Wide Range ◽  
Cortical Pyramidal Neurons ◽  
Cellular Phenotypes

The architecture of dendritic arbors contributes to neuronal connectivity in the brain. Conversely, abnormalities in dendrites have been reported in multiple mental disorders and are thought to contribute to pathogenesis. Rare copy number variations (CNVs) are genetic alterations that are associated with a wide range of mental disorders and are highly penetrant. The 16p11.2 microduplication is one of the CNVs most strongly associated with schizophrenia and autism, spanning multiple genes possibly involved in synaptic neurotransmission. However, disease-relevant cellular phenotypes of 16p11.2 microduplication and the driver gene(s) remain to be identified. We found increased dendritic arborization in isolated cortical pyramidal neurons from a mouse model of 16p11.2 duplication (dp/+). Network analysis identified MAPK3, which encodes ERK1 MAP kinase, as the most topologically important hub in protein–protein interaction networks within the 16p11.2 region and broader gene networks of schizophrenia-associated CNVs. Pharmacological targeting of ERK reversed dendritic alterations associated with dp/+ neurons, outlining a strategy for the analysis and reversal of cellular phenotypes in CNV-related psychiatric disorders.

scholarly journals Mesothelin blockage by Amatuximab suppresses cell invasiveness, enhances gemcitabine sensitivity and regulates cancer cell stemness in mesothelin-positive pancreatic cancer cells

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Fumihiko Matsuzawa ◽  
Hirofumi Kamachi ◽  
Tatsuzo Mizukami ◽  
Takahiro Einama ◽  
Futoshi Kawamata ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Morphological Changes ◽  
Pancreatic Cancer Cells ◽  
Cell Invasiveness ◽  
And Migration ◽  
Migration Capacity

Abstract Background Mesothelin is a 40-kDa glycoprotein that is highly overexpressed in various types of cancers, however molecular mechanism of mesothelin has not been well-known. Amatuximab is a chimeric monoclonal IgG1/k antibody targeting mesothelin. We recently demonstrated that the combine therapy of Amatuximab and gemcitabine was effective for peritonitis of pancreatic cancer in mouse model. Methods We discover the role and potential mechanism of mesothelin blockage by Amatuximab in human pancreatic cells both expressing high or low level of mesothelin in vitro experiment and peritonitis mouse model of pancreatic cancer. Results Mesothelin blockage by Amatuximab lead to suppression of invasiveness and migration capacity in AsPC-1 and Capan-2 (high mesothelin expression) and reduce levels of pMET expression. The combination of Amatuximab and gemcitabine suppressed proliferation of AsPC-1 and Capan-2 more strongly than gemcitabine alone. These phenomena were not observed in Panc-1 and MIA Paca-2 (Mesothelin low expression). We previously demonstrated that Amatuximab reduced the peritoneal mass in mouse AsPC-1 peritonitis model and induced sherbet-like cancer cell aggregates, which were vanished by gemcitabine. In this study, we showed that the cancer stem cell related molecule such as ALDH1, CD44, c-MET, as well as proliferation related molecules, were suppressed in sherbet-like aggregates, but once sherbet-like aggregates attached to peritoneum, they expressed these molecules strongly without the morphological changes. Conclusions Our work suggested that Amatuximab inhibits the adhesion of cancer cells to peritoneum and suppresses the stemness and viability of those, that lead to enhance the sensitivity for gemcitabine.

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