Anti-CRMP2 antibody induces anxiety-like behavior and increases pyramidal neuron excitability in mice.

BACKGROUND: We have previously identified auto-antibody (Ab) to collapsin response mediator protein 2 (CRMP2) in patients with encephalitis. The present study aims to evaluate the pathogenic effects of anti-CRMP2 Ab. METHODS: Recombinant CRMP2 protein was injected subcutaneously into mice to establish an active immune mouse model with anti-CRMP2 Ab. Behavioral assessments, histopathological staining, and electrophysiological testing were performed to identify any pathogenic changes. RESULTS: The mice exhibited signs of impaired motor coordination four weeks post-immunization of CRMP2 protein. Moreover, CRMP2 immunized mice for eight weeks showed anxiety-like behaviors indicating by tests of open field and the elevated plus maze. After incubating the CA1 region of hippocampal brain section with the sera from CRMP2 immunized mice, the whole-cell path-clamp recordings showed increased excitability of pyramidal neurons. However, no obvious inflammation and infiltration of immune cells were observed by histopathological analysis. Western blot showed that the phosphorylation levels of CRMP2-Thr514 and -Ser522 were not affected. CONCLUSION: In an active immunization model with CRMP2 protein, impaired coordination and anxiety-like behaviors were observed. Also, anti-CRMP2 Abs containing sera heightened the excitability of hippocampal pyramidal neurons in vitro, which imply the pathogenic effects of anti-CRMP2 Ab.

Glutamate receptor-interacting protein 1 in D1- and D2-dopamine receptor-expressing medium spiny neurons differentially regulates cocaine acquisition, reinstatement, and associated spine plasticity.

Background: The nucleus accumbens (NAc) is involved in the expression of cocaine addictive phenotypes, including acquisition, extinction, and reinstatement. In the NAc, D1-medium spiny neurons (MSNs) encode cocaine reward, whereas D2-MSNs encode aversive responses in drug addiction. Glutamate receptor-interacting protein 1 (GRIP1) is known to be associated with cocaine addiction, but the role of GRIP1 in D1-MSNs and D2-MSNs of the NAc in cocaine acquisition and reinstatement remains unknown. Methods: A conditioned place preference apparatus was used to establish cocaine acquisition, extinction, and reinstatement in mouse models. GRIP1 expression was evaluated using Western blotting. Furthermore, GRIP1-siRNA and GRIP1 overexpression lentivirus were used to interfere with GRIP1 in the NAc. After the behavioral test, green fluorescent protein immunostaining of brain slices was used to detect spine density. Results: GRIP1 expression decreased during cocaine acquisition and reinstatement. GRIP1-siRNA enhanced cocaine-induced CPP behavior in acquisition and reinstatement and regulated associated spine plasticity. Importantly, the decreased GRIP1 expression that mediated cocaine acquisition and reinstatement was mainly driven by the interference of the GRIP1-GluA2 interaction in D1-MSNs and could be blocked by the interference of the GRIP1-GluA2 interaction in D2-MSNs. Interference with the GRIP1-GluA2 interaction in D1- and D2-MSNs decreased spine density in D1- and D2-MSNs, respectively. Conclusion: GRIP1 in D1- and D2-MSNs of the NAc differentially modulates cocaine acquisition and reinstatement. GRIP1 downregulation in D1-MSNs has a positive effect on cocaine acquisition and reinstatement, while GRIP1 downregulation in D2-MSNs has a negative effect. Additionally, GRIP1 downregulation in D1-MSNs plays a leading role in cocaine acquisition and reinstatement.

Analysis of Diurnal Variations in Heart Rate: Potential Applications for Chronobiology and Cardiovascular Medicine.

Circadian factors likely influence the occurrence, development, therapy, and prognosis of cardiovascular diseases (CVDs). To determine the association between the heart rate (HR) diurnal parameters and CVD risks, we designed an analytical strategy to detect diurnal rhythms of HR using longitudinal data collected by clinically used Holter monitors and wearable devices. By combining in-house developed algorithms with existing analytical tools, we obtained trough phase and nocturnal variation in HR for different purposes. The analytical strategy is robust and also sensitive enough to identify variations in HR rhythms influenced by multiple effectors such as jet lag, geological location and altitude, and age from total 211 volunteers. A total of 10,094 sets of 24-h Holter ECG data were analyzed by stepwise partial correlation to determine the critical points of HR trough phase and nocturnal variation. The following HR diurnal patterns correlate with high CVD risk: arrhythmic pattern, anti-phase pattern, rhythmic patterns with trough phase less than 0 (extremely advanced diurnal pattern) or more than 5 (extremely delayed diurnal pattern), and nocturnal variation less than 2.75 (extremely low) or more than 26 (extremely high). In addition, HR trough phases from wearable devices were nearly identical to those from 24-h Holter monitoring from 12 volunteers by linear correlation and Bland-Altman analysis. Our analytical system provides useful information to identify functional diurnal patterns and parameters by monitoring personalized, HR-based diurnal changes. These findings have important implications for understanding how a regular heart diurnal pattern benefits cardiac function and raising the possibility of non-pharmacological intervention against circadian related CVDs. With the rapid expansion of wearable devices, public cardiovascular health can be promoted if the analytical strategy is widely applied.

Anatomic Measurement and Variability Analysis of the Anterior Talofibular Ligament and Calcaneofibular Ligament of the Ankle.

BACKGROUND: The anterior talofibular ligament (ATFL) and calcaneofibular ligament (CFL) contribute greatly to the overall stability of the ankle joint; however, ATFL and combined ATFL-CFL sprains are common. Anatomic reconstruction of the lateral collateral ligament with grafts has been proposed for patients with poor tissue quality or inadequate local tissue. Anatomic reconstruction of the lateral ankle ligaments requires a good understanding of their anatomic location. PURPOSE: To describe the anatomy of the ATFL and CFL ligaments quantitatively and qualitatively and explore the relationship of some morphological parameters. STUDY DESIGN: Descriptive laboratory study. METHODS: A total of 66 adult ankle specimens were analyzed for ATFL band type, origin, length, width, thickness, and angle between the ATFL and CFL, and 73 adult ankle specimens were used for measuring the origin of the CFL. The coefficient of variation was used to describe and compare the respective variability of angle, length, width, and thickness. The origin of the ATFL was labeled as point A, and the leading edge of the CFL intersection with the articular surface of the calcaneus was considered point B. RESULTS: The ATFL had a variable number of bands. A high degree of variability (coefficient of variation >0.2) was seen for most morphological measurements of the ATFL. In addition, the length of distance AB also varied. The CFL originated at the tip of the fibula in only 9% of specimens. It was found more commonly at the anterior border of the lateral malleolus (4.94 ± 1.70 mm from the tip). The angle between the ATFL and CFL was consistent at 100° to 105º. CONCLUSION: A fair amount of variability of ATFL length, width, and thickness were found in our study, with less variability in the ATFL-CFL angle. Most CFLs attached anterior to the tip of the fibula. CLINICAL RELEVANCE: Providing relevant anatomic data of ATFL and CFL is important in ensuring proper surgical treatment of ankle joint injuries.