KCC2 downregulation after sciatic nerve injury enhances motor function recovery.

Injury to mature neurons induces downregulated KCC2 expression and activity, resulting in elevated intracellular [Cl-] and depolarized GABAergic signaling. This phenotype mirrors immature neurons wherein GABA-evoked depolarizations facilitate neuronal circuit maturation. Thus, injury-induced KCC2 downregulation is broadly speculated to similarly facilitate neuronal circuit repair. We test this hypothesis in spinal cord motoneurons injured by sciatic nerve crush, using transgenic (CaMKII-KCC2) mice wherein conditional CaMKIIα promoter-KCC2 expression coupling selectively prevents injury-induced KCC2 downregulation. We demonstrate, via an accelerating rotarod assay, impaired motor function recovery in CaMKII-KCC2 mice relative to wild-type mice. Across both cohorts, we observe similar motoneuron survival and re-innervation rates, but differing post-injury reorganization patterns of synaptic input to motoneuron somas-for wild-type, both VGLUT1-positive (excitatory) and GAD67-positive (inhibitory) terminal counts decrease; for CaMKII-KCC2, only VGLUT1-positive terminal counts decrease. Finally, we recapitulate the impaired motor function recovery of CaMKII-KCC2 mice in wild-type mice by administering local spinal cord injections of bicuculline (GABAA receptor blockade) or bumetanide (lowers intracellular [Cl-] by NKCC1 blockade) during the early post-injury period. Thus, our results provide direct evidence that injury-induced KCC2 downregulation enhances motor function recovery and suggest an underlying mechanism of depolarizing GABAergic signaling driving adaptive reconfiguration of presynaptic GABAergic input.

Identifying high-risk population of depression: association between metabolic syndrome and depression using a health checkup and claims database.

Depression and metabolic syndrome (MetS) are correlated, leading to an increased healthcare burden and decreased productivity. We aimed to investigate the association between MetS-related factors and depression using a health checkup and claims database. Individuals aged 18-75 years who underwent health examinations between 2014 and 2019 were enrolled in the study. Among 76,277 participants, "ever" and "incident" antidepressant users exhibited worse metabolic profiles and were more likely to be prescribed hypnotics and anxiolytics than "never" users. In a nested case-control study with a 1:10 ratio of incident users to controls, MetS was associated with incident antidepressant use (odds ratio, 1.53 [95% confidence interval 1.24-1.88]) adjusted for lifestyle information obtained from a self-administered questionnaire, medical history, and medications. Other metabolic traits also showed significant associations: body mass index (1.04 [1.02-1.06]), abdominal circumference per 10 cm (1.17 [1.08-1.27]), high blood pressure (1.17 [1.00-1.37]), glucose intolerance (1.29 [1.05-1.58]), and dyslipidemia (1.27 [1.08-1.51]). A bodyweight increase > 10 kg from age 20 years (1.46 [1.25-1.70]) was also significantly associated with incident antidepressant use. In conclusion, metabolic abnormalities were associated with incident antidepressant use and can be useful in identifying populations at high risk of depression.

A Mobile Health-Based Disease Management Program Improves Blood Pressure in People With Multiple Lifestyle-Related Diseases at Risk of Developing Vascular Disease　- A Retrospective Observational Study.

Background: The overlap of multiple lifestyle-related diseases increases the risk of vascular diseases. This study investigated the effects of a mobile health (mHealth)-based disease management program on blood pressure and the safety of this program in people with multiple lifestyle-related diseases at risk of developing vascular disease. Methods and Results: This retrospective observational study was conducted using secondary data collected by PREVENT Inc. People with a full history of hypertension, diabetes, and dyslipidemia and who participated in a 6-month mHealth-based disease management program were included in the study. The primary outcome was blood pressure. Adverse events during the program were investigated to evaluate safety. In total, 125 participants (mean [±SD] age 55.3±6.2 years) were examined. Systolic and diastolic blood pressure were significantly lower after the intervention than at baseline (systolic blood pressure, 128.0±12.3 vs. 131.9±12.7 mmHg [P<0.001]; diastolic blood pressure, 81.2±9.3 vs. 83.6±8.9 mmHg; P=0.003). No serious adverse events occurred during the program. Conclusions: The present results indicate that the mHealth-based disease management program may reduce blood pressure in people with multiple lifestyle-related diseases at risk of developing vascular disease and that the program is safe. These findings will help shape future health instructions using mHealth-based interventions.

Down-regulation of KCC2 expression and phosphorylation in motoneurons, and increases the number of in primary afferent projections to motoneurons in mice with post-stroke spasticity.

Spasticity obstructs motor function recovery post-stroke, and has been reported to occur in spinal cord injury and electrophysiological studies. The purpose of the present study was to assess spinal cord circuit spasticity in post-stroke mice. At 3, 7, 21, and 42 d after photothrombotic ischemic cortical injury in C57BL/6J mice, we observed decreased rate-dependent depression (RDD) of the Hoffmann reflex (H reflex) in the affected forelimb of mice compared with the limbs of sham mice and the non-affected forelimb. This finding suggests a hyper-excitable stretch reflex in the affected forelimb. We then performed immunohistochemical and western blot analyses to examine the expression of the potassium-chloride cotransporter 2 (KCC2) and phosphorylation of the KCC2 serine residue, 940 (S940), since this is the main chloride extruder that affects neuronal excitability. We also performed immunohistochemical analyses on the number of vesicular glutamate transporter 1 (vGluT1)-positive boutons to count the number of Ia afferent fibers that connect to motoneurons. Western bolts revealed that, compared with sham mice, experimental mice had significantly reduced KCC2 expression at 7 d post-stroke, and dephosphorylated S940 at 3 and 7 d post-stroke in motoneuron plasma membranes. We also observed a lower density of KCC2-positive areas in the plasma membrane of motoneurons at 3 and 7 d post-stroke. However, western blot and immunohistochemical analyses revealed that there were no differences between groups 21 and 42 d post-stroke, respectively. In addition, at 7 and 42 d post-stroke, experimental mice exhibited a significant increase in vGluT1 boutons compared with sham mice. Our findings suggest that both the down-regulation of KCC2 and increases in Ia afferent fibers are involved in post-stroke spasticity.