Imbalance between hippocampal projection cell and parvalbumin interneuron architecture increases epileptic susceptibility in mouse model of methyl CpG binding protein 2 duplication syndrome.

OBJECTIVE: Methyl CpG-binding protein 2 (MECP2) duplication syndrome is a rare X-linked genomic disorder affecting predominantly males, which is usually manifested as epilepsy and autism spectrum disorder (ASD) comorbidity. The transgenic line MeCP2Tg1 was used for mimicking MECP2 duplication syndrome and showed autism-epilepsy co-occurrence. Previous works suggested that the excitatory/inhibitory (E/I) imbalance is a potential common mechanism for both epilepsy and ASD. The projection neurons and parvalbumin (PV) interneurons account for the majority of E/I balance in the hippocampus. Therefore, we explored how structural changes of projection and PV+ neurons occur in the hippocampus of MeCP2Tg1 mice and whether these morphological changes contribute to epilepsy susceptibility. METHODS: We used the interneuron Designer receptors exclusively activated by designer drugs mouse model to inhibit inhibitory neurons in the hippocampus to verify the epilepsy susceptibility of MeCP2Tg1 (FVB, an inbred strain named as sensitivity to Friend leukemia virus) mice. Electroencephalograms were recorded for the definition of seizure. We performed retro-orbital injection of virus in MeCP2Tg1 (FVB):CaMKIIα-Cre (C57BL/6) mice or MeCP2Tg1:PV-Cre (C57BL/6) mice and their littermate controls to specifically label projection and PV+ neurons for structural analysis. RESULTS: Epilepsy susceptibility was increased in MeCP2Tg1 mice. There was a reduced number of PV neurons and reduced dendritic complexity in the hippocampus of MeCP2Tg1 mice. The dendritic complexity in MeCP2Tg1 mice was increased compared to wild-type mice, and total dendritic spine density in dentate gyrus of MeCP2Tg1 mice was also increased. Total dendritic spine density was increased in CA1 of MeCP2Tg1 mice. SIGNIFICANCE: Overexpression of MeCP2 may disrupt crucial signaling pathways, resulting in decreased dendritic complexity of PV interneurons and increased dendritic spine density of projection neurons. This reciprocal modulation of excitatory and inhibitory neuronal structures associated with MeCP2 implies its significance as a potential target in the development of epilepsy and offers a novel perspective on the co-occurrence of autism and epilepsy.

ITPR2 Mediated Calcium Homeostasis in Oligodendrocytes is Essential for Myelination and Involved in Depressive-Like Behavior in Adolescent Mice.

Ca2+ signaling is essential for oligodendrocyte (OL) development and myelin formation. Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2) is an endoplasmic reticulum calcium channel and shows stage-dependent high levels in postmitotic oligodendrocyte precursor cells (OPCs). The role and potential mechanism of ITPR2 in OLs remain unclear. In this study, it is revealed that loss of Itpr2 in OLs disturbs Ca2+ homeostasis and inhibits myelination in adolescent mice. Animals with OL-specific deletion of Itpr2 exhibit anxiety/depressive-like behaviors and manifest with interrupted OPC proliferation, leading to fewer mature OLs in the brain. Detailed transcriptome profiling and signal pathway analysis suggest that MAPK/ERK-CDK6/cyclin D1 axis underlies the interfered cell cycle progression in Itpr2 ablated OPCs. Besides, blocking MAPK/ERK pathway significantly improves the delayed OPC differentiation and myelination in Itpr2 mutant. Notably, the resting [Ca2+]i is increased in Itpr2 ablated OPCs, with the elevation of several plasma calcium channels. Antagonists against these plasma calcium channels can normalize the resting [Ca2+]i level and enhance lineage progression in Itpr2-ablated OPCs. Together, the findings reveal novel insights for calcium homeostasis in manipulating developmental transition from OPCs to pre-OLs; additionally, the involvement of OLs-originated ITPR2 in depressive behaviors provides new therapeutic strategies to alleviate myelin-associated psychiatric disorders.

Glutamatergic Neurons in the Zona Incerta Modulate Pain and Itch Behaviors in Mice.

Emerging evidence suggest that parvalbumin neurons in zona incerta (ZI) modulate pain and itch behavior in opposite manners. However, the role of ZI glutamatergic neurons, a unique incertal neuronal subpopulation residing in the caudal division, in pain and itch modulation remains unknown. In the present study, by combining chemogenetic manipulation, fiber photometry, and behavioral tests, we proved that incertal glutamatergic neurons served as an endogenous negative diencephalic modulator for both pain and itch processing. We demonstrated that ZI vesicular glutamate transporter 2 (VGluT2) neurons exhibited increased calcium signal upon hindpaw withdrawal in response to experimental mechanical and thermal stimuli. Behavioral tests further showed that pharmacogenetic activation of this specific type of neurons reduced nocifensive withdrawal responses in both naïve and inflammatory pain mice. Similar neural activity and modulatory role of ZI VGluT2 neurons were also observed upon histaminergic and non-histaminergic acute itch stimuli. Together, our study would expedite our understandings of brain mechanisms underlying somatosensory processing and modulation, and supply a novel therapeutic target for the management of chronic pain and itch disorders.

The risk factors of thrombus formation and the effect of catheter ablation on repetitive thrombus formation in patients with atrial fibrillation: a single center retrospective study in China.

BACKGROUND: Atrial fibrillation (AF) predisposes patients to the formation of atrial thrombi. The CHA2DS2-VASc score does not include all risk factors for atrial thrombosis. The present study is designed to explore the influencing factors of thrombus formation in patients with AF and to investigate the effect of catheter ablation (CA) on recurrent thrombosis in patients with a history of intracardiac thrombus. METHODS: (1) This study consisted of 1726 patients that underwent CA, among which 58 patients had a history of intracardiac thrombus prior to CA. The risk factors for thrombus formation were explored by comparing the baseline clinical characteristics of patients with and without atrial thrombus. (2) The left atrial appendage flow velocity (LAAFV) in patients with a history of intracardiac thrombus who were willing to undergo transesophageal echocardiography (TEE) at the latest follow-up were examined, and comparisons of the LAAFV was made before and after CA. RESULTS: The median follow-up period is 13 months. Persistent AF was found to be the only independent risk factor affecting the formation of atrial thrombus among the investigated factors (OR 3.152; 95%CI 1.806-5.500; p < 0.001). Twenty-seven patients agreed to undergo TEE during follow-up, no clinical ischemic stroke events were recorded, no recurrent intracardiac thrombus formation was detected in patients, 15 patients maintained sinus rhythm (55.6%) during follow-up; successful CA significantly increased LAAFV (difference between latest evaluation prior to CA 17.46 ± 14.81 cm/s, p < 0.001). CONCLUSIONS: Persistent AF is the only independent risk factor for thrombus formation. Successful CA may improve the LAAFV and thereby decrease the risk of intracardiac thrombus formation.

Efficacy and Safety of NOACs Compared With VKAs for Patients With Atrial Fibrillation After Transcatheter Aortic Valve Implantation: A System Review and Meta-Analysis.

Novel oral anticoagulants (NOACs) are preferentially recommended in patients with nonvalvular atrial fibrillation (AF) for stroke prevention over vitamin K antagonists (VKAs). However, the evidence regarding the efficacy and safety of NOACs versus VKAs after transcatheter aortic valve implantation (TAVI) in patients with AF is very rare. Pubmed, Embase, Web of science, and Cochrane Databases were searched for eligible studies published before May 19, 2022. A total of 11 studies were included in this meta-analysis involving 27 107 patients. Regarding primary outcomes, there were no differences between NOACs and VKAs in all-cause mortality (RR: 0.84, 95% CI: (0.69, 1.02)) and stroke (RR: 1.00, 95% CI: (0.85, 1.19)). With respect to secondary outcomes, NOACs were associated with reduced incidence of bleeding (RR: 0.77, 95% CI: (0.71, 0.83)) and intracranial bleeding (RR: 0.57, 95% CI: (0.39, 0.83)), whereas no significant differences were found in major or life-threatening bleeding (RR: 0.98, 95% CI: (0.82, 1.17)) and myocardial infarction (RR: 1.37, 95% CI: (0.83, 2.26)). Our meta-analysis revealed the safety and efficacy of NOACs may be superior to VKAs in AF patients undergoing TAVI.

Understanding the scope of intracardiac echocardiography in catheter ablation of ventricular arrhythmia.

Over the last few decades, catheter ablation has emerged as the first-line treatment for ventricular arrhythmias. However, detailed knowledge of cardiac anatomy during the surgery remains the prerequisite for successful ablation. Intracardiac echocardiography (ICE) is a unique imaging technique, which provides real-time visualization of cardiac structures, and is superior to other imaging modalities in terms of precise display of cardiac tissue characteristics as well as the orientation of anatomical landmarks. This article aimed to introduce the various advantages and limitations of ICE in the ablation of ventricular arrhythmias.

Association of acetaldehyde dehydrogenase 2 rs671 polymorphism with the occurrence and progression of atrial fibrillation.

Background: Acetaldehyde dehydrogenase 2 (ALDH2) is an essential enzyme in alcohol metabolism, playing a vital function in resisting oxidative stress. Lots of gene variants have been associated with atrial fibrillation (AF), among which the association between ALDH2 rs671 polymorphism and AF is variable. This study aimed to investigate the relationship between ALDH2 rs671 polymorphism and AF occurrence or progression and AF recurrence after catheter ablation. Methods: A total of 924 subjects were enrolled in the study. The ALDH2 genotypes are composed of wild-type homozygotes (ALDH2*1/*1), heterozygotes (ALDH2*1/*2), and mutant homozygotes (ALDH2*2/*2), in which the genotypes ALDH2*1/*2 and ALDH2*2/*2 are combined into the ALDH2*2. Univariate and multivariate logistic regression analyses were performed to investigate the association between ALDH2*2 and AF occurrence and progression. COX regression analysis was used to explore the association of ALDH2*2 with AF recurrence after catheter ablation. Results: The prevalence of AF differed significantly between the ALDH2*2 group (102/251) and ALDH2*1/*1 group (330/673) (P = 0.023). For AF occurrence, in the univariate analysis, alcohol consumption was a risk factors (OR: 1.503, P = 0.003), whereas ALDH2*2 was a protective factor (OR: 0.712, P = 0.023). In the multivariate analysis, alcohol consumption (P = 0.156) and ALDH2*2 (P = 0.096) were no longer independent factors. ALDH2*2 with non-drinking was associated with a decreased AF occurrence (OR: 0.65, P = 0.021), whereas ALDH2*2 with drinking was not (P = 0.365). For AF progression, multivariate analysis revealed ALDH2*2 could promote persistent AF in female AF patients (OR: 2.643, P = 0.008). Cox regression analysis suggested that ALDH2*2 (P = 0.752) was not a risk factor for AF recurrence after catheter ablation during a median 6 months follow-up. Conclusion: While ALDH2*2 was not directly related to AF, ALDH2*2 with non-drinking was associated with a decreased incidence of AF. ALDH2*2 may accelerate AF progression in female patients, increasing the likelihood of developing persistent AF. Therefore, individuals with ALDH2*2 should refrain from consuming alcohol to decrease the onset and progression of AF.

A prediction model of atrial fibrillation recurrence after first catheter ablation by a nomogram: HASBLP score.

Background: At present, catheter ablation is an effective method for rhythm control in patients with atrial fibrillation (AF). However, AF recurrence is an inevitable problem after catheter ablation. To identify patients who are prone to relapse, we developed a predictive model that allows clinicians to closely monitor these patients and treat them with different personalized treatment plans. Materials and methods: A total of 1,065 patients who underwent AF catheter ablation between January 2015 and December 2018 were consecutively included in this study, which examines the results of a 2-year follow-up. Patients with AF were divided into development cohort and validation cohort. Univariate and multivariate analyses were carried out on the potential risk factors. Specific risk factors were used to draw the nomogram according to the above results. Finally, we verified the performance of our model compared with CHADS2 and CHA2DS2-Vasc scores by receiver operating characteristic (ROC) curve and calibration curve and plotted the decision analysis curve (DAC). Results: A total of 316 patients experienced AF recurrence. After univariate and multivariate analyses, AF history (H), age (A), snoring (S), body mass index (BMI) (B), anteroposterior diameter of left atrial (LA) (L), and persistent AF (P) were included in our prediction model. Our model showed a better performance compared with CHADS2 and CHA2DS2-Vasc scores, and the area under ROC curve (95%CI) was 0.7668 (0.7298-0.8037) vs. 0.6225 (0.5783-0.6666) and 0.6267 (0.5836-0.6717). Conclusion: We established a nomogram (HASBLP score) for predicting AF recurrence after the first catheter ablation at a 2-year follow-up, which can be used as a tool to guide future follow-up of patients. However, its usefulness needs further validation.

Case report: Double-chambered right ventricle diagnosed in a middle-aged female with hypertrophic cardiomyopathy and atrial flutter: A rare case.

Double-chambered right ventricle (DCRV) is a rare congenital heart defect in adults, manifesting with progressive right ventricular outflow tract obstruction. We describe the first case of DCRV coexisting with hypertrophic cardiomyopathy, which is complicated by atrial flutter. A middle-aged woman with recurrent symptomatic atrial flutter who had previously been diagnosed with biventricular hypertrophic cardiomyopathy was admitted to our department. Echocardiography and cardiac magnetic resonance revealed asymmetrical interventricular septal hypertrophy, and abnormal muscle bundles within the right ventricle, generating an obstructive gradient. Genetic testing detected a hypertrophic cardiomyopathy-associated mutation: MYH7, c.4135G > A, p. Ala1379Thr. A diagnosis of DCRV complicated by hypertrophic cardiomyopathy and atrial flutter was made. Surgical intervention was performed, which included radiofrequency ablation, removal of abnormal muscle bundles, and ventricular septal defect repair. Intraoperative transesophageal echocardiography demonstrated the well-corrected right ventricular outflow tract. Free of early postoperative complications, the patient was discharged in sinus rhythm on the 11th day after the surgery. Unfortunately, the patient died from a sudden death 38 days following the surgery. In conclusion, the coexistence of DCRV with hypertrophic cardiomyopathy in patients is an uncommon condition. The present case highlights the importance of diagnostic imaging in the management of this disorder.

Can intracardiac echocardiography completely replace transesophageal echocardiography to guide left atrial appendage closure?-The comparisons of intracardiac echocardiography with transesophageal echocardiography.

Left atrial appendage closure (LAAC) is an effective means of preventing ischemic stroke in patients with nonvalvular atrial fibrillation. Transesophageal echocardiography (TEE) is the primary imaging technique to guide LAAC. Its shortcomings, namely the use of general anesthesia and tracheal intubation, inevitably increase procedural risks. Intracardiac echocardiography (ICE), a novel imaging modality for guiding LAAC, has proven more advantageous over TEE due to use of local anesthesia, shortened procedural time, and reduced radiation exposure. This review highlights the differences between ICE and TEE guided LAAC, aiming to provide a reference for clinical decision-making.

Excitatory and Inhibitory Synaptic Imbalance Caused by Brain-Derived Neurotrophic Factor Deficits During Development in a Valproic Acid Mouse Model of Autism.

Environmental factors, such as medication during pregnancy, are one of the major causes of autism spectrum disorder (ASD). Valproic acid (VPA) intake during pregnancy has been reported to dramatically elevate autism risk in offspring. Recently, researchers have proposed that VPA exposure could induce excitatory or inhibitory synaptic dysfunction. However, it remains to be determined whether and how alterations in the excitatory/inhibitory (E/I) balance contribute to VPA-induced ASD in a mouse model. In the present study, we explored changes in the E/I balance during different developmental periods in a VPA mouse model. We found that typical markers of pre- and postsynaptic excitatory and inhibitory function involved in E/I balance markedly decreased during development, reflecting difficulties in the development of synaptic plasticity in VPA-exposed mice. The expression of brain-derived neurotrophic factor (BDNF), a neurotrophin that promotes the formation and maturation of glutamatergic and GABAergic synapses during postnatal development, was severely reduced in the VPA-exposed group. Treatment with exogenous BDNF during the critical E/I imbalance period rescued synaptic functions and autism-like behaviors, such as social defects. With these results, we experimentally showed that social dysfunction in the VPA mouse model of autism might be caused by E/I imbalance stemming from BDNF deficits during the developmental stage.

Parvalbumin Neurons in Zona Incerta Regulate Itch in Mice.

Pain and itch are intricately entangled at both circuitry and behavioral levels. Emerging evidence indicates that parvalbumin (PV)-expressing neurons in zona incerta (ZI) are critical for promoting nocifensive behaviors. However, the role of these neurons in itch modulation remains elusive. Herein, by combining FOS immunostaining, fiber photometry, and chemogenetic manipulation, we reveal that ZI PV neurons act as an endogenous negative diencephalic modulator for itch processing. Morphological data showed that both histamine and chloroquine stimuli induced FOS expression in ZI PV neurons. The activation of these neurons was further supported by the increased calcium signal upon scratching behavior evoked by acute itch. Behavioral data further indicated that chemogenetic activation of these neurons reduced scratching behaviors related to histaminergic and non-histaminergic acute itch. Similar neural activity and modulatory role of ZI PV neurons were seen in mice with chronic itch induced by atopic dermatitis. Together, our study provides direct evidence for the role of ZI PV neurons in regulating itch, and identifies a potential target for the remedy of chronic itch.

An auto real-time jump tagging system for exploring stereotyped jumping behavior in mice.

The jump is one of the common stereotyped behavior in rodents which can be found in certain types of disease models, such as addiction. It can be easily identified by the human eye. However, it is difficult to be tagged in real-time by manual operation, which limits the detailed exploration of its neural mechanisms with the new techniques, such as fiber photometry recording. Here we introduced an auto real-time jump tagging system (Art-JT system) to record the jump based on online monitoring the pressure changes of the floor in which the mouse is free exploring. Meanwhile, the Art-JT system can send the digital signal of the jump timing to the external device for tagging the events in the fiber photometry system. We tested it with the mice induced by Naloxone precipitated withdrawal jumping and found that it could accurately record the jump events and provide several detailed parameters of the jump. We also confirmed that the jump was correlated with the medial prefrontal cortex and primary motor cortex neuronal activities by combining the Art-JT system, GCaMP6 mice, and fiber photometry system. Our results suggested that the Art-JT system may be a powerful tool for recording and analyzing jumps efficiently and helping us to understand stereotyped behavior.