Neonatal maternal separation delays the GABA excitatory-to-inhibitory functional switch by inhibiting KCC2 expression.

The excitatory-to-inhibitory functional switch of γ-aminobutyric acid (GABA; GABA switch), which normally occurs in the first to the second postnatal week in the hippocampus, is necessary for the development of appropriate central nervous system function. A deficit in GABAergic inhibitory function could cause excitatory/inhibitory (E/I) neuron imbalance that is found in many neurodegenerative disorders. In the present study, we examined whether neonatal stress can affect the timing of the GABA functional switch and cause disorders during adolescence. Neonatal stress was induced in C57BL/6J male mouse pups by maternal separation (MS) on postnatal days (PND) 1-21. Histological quantification of K+-Cl- co-transporter (KCC2) and Ca2+ imaging were performed to examine the timing of the GABA switch during the MS period. To evaluate the influence of neonatal MS on adolescent hippocampal function, we quantified KCC2 expression and evaluated hippocampal-related behavioral tasks at PND35-38. We showed that MS delayed the timing of the GABA switch in the hippocampus and inhibited the increase in membrane KCC2 expression, with KCC2 expression inhibition persisting until adolescence. Behavioral tests showed impaired cognition, declined attention, hyperlocomotion, and aggressive character in maternally separated mice. Taken together, our results show that neonatal stress delayed the timing of the GABA switch, which could change the E/I balance and cause neurodegenerative disorders in later life.

Evaluation of maxillary central incisors on the noncleft and cleft sides in patients with unilateral cleft lip and palate-Part 1: Relationship between root length and orthodontic tooth movement.

OBJECTIVES: To measure the root lengths of maxillary central incisors (U1) and evaluate the relationship among U1 root length, tooth movement, and type of treatment appliance in patients with unilateral cleft lip and palate over a long-term follow-up period. MATERIALS AND METHODS: Occlusal radiographs of 30 patients with unilateral cleft lip and palate, acquired less than 6 months before secondary alveolar bone grafting (SBG, T1) and after edgewise treatment (T2), were measured for U1 root length (R1 and R2, root lengths at T1 and T2, respectively). Frontal and lateral cephalometric radiographs acquired at eruption of U1 (T0), T1, and T2 were evaluated to determine the inclination and position of U1. RESULTS: The average values of R1 and R2 on the cleft side were significantly lower than those on the noncleft side. Frontal cephalometric analysis revealed that the horizontal distance of the root apex from the median vertical line at T0 on the cleft side was significantly smaller than that on the noncleft side and was correlated with short U1 root length on the cleft side. On the other hand, R1 in patients treated with maxillary protraction appliances between T0 and T1 was significantly shorter than that in patients without maxillary protraction appliances. However, none of the changes in cephalometric measurements were correlated with root length. CONCLUSIONS: In patients with unilateral cleft lip and palate, the short root length of cleft-adjacent central incisors might be associated with the horizontal position of the root apex. In addition, orthodontic treatment with a maxillary protraction appliance before secondary alveolar bone grafting might be associated with short U1 root length.

Evaluation of maxillary central incisors on the noncleft and cleft sides in patients with unilateral cleft lip and palate-Part 2: Relationship between root resorption, horizontal tooth movement, and quantity of grafted autogenous bone.

OBJECTIVE: To evaluate the relationship between external apical root resorption (EARR) of the maxillary central incisors (U1), horizontal orthodontic tooth movement, and quantity of grafted bone in subjects with unilateral cleft lip and palate (UCLP) over an average duration of 8 years. MATERIALS AND METHODS: Thirty subjects with UCLP were evaluated for EARR of U1 after edgewise treatment (T2). The teeth were classified as having no EARR, moderate EARR (combined into "no/moderate" EARR), or severe EARR. Frontal cephalometric radiographs acquired at eruption of U1 (T0), less than 6 months before secondary alveolar bone grafting (T1), and T2 were evaluated to determine the horizontal inclination (U1-axis angle) and distance of the root apex from the median line (U1-root-VL distance). On the cleft side, the quantities of grafted bone at less than 12 months postsecondary bone grafting and at T2 were evaluated using the alveolar bone graft (ABG) scale. RESULTS: Cleft-adjacent teeth exhibited more severe EARR than did teeth on the noncleft side. The cleft side exhibited greater changes in U1-axis angle and U1-root-VL distance between T0 and T2 than did the noncleft side. On the cleft side, the ABG score at T2 in the severe EARR group was significantly lower than that in the no/moderate EARR group. These measurements were correlated with EARR grade. CONCLUSIONS: Cleft-adjacent U1 exhibited more severe EARR than did the U1 on the noncleft side, which might be associated with orthodontic treatment-induced changes in horizontal inclination and root apex movement. On the cleft side, severity of EARR may be correlated with the success of ABG.

A relation between osteoclastogenesis inhibition and membrane-type estrogen receptor GPR30.

Disruption of the cooperative balance between osteoblasts and osteoclasts causes various bone disorders, some of which are because of abnormal osteoclast recruitment. Osteoporosis, one of the bone disorders, is not effectively treated by currently available medicines. In addition to the development of novel drugs for palliative treatment, the exploitation of novel compounds for preventive treatment is important in an aging society. Quercetin, a major flavonoid found in many fruits and vegetables, has been expected to inhibit cancer and prevent several diseases because of its anti-inflammatory and estrogenic functions. It has been reported that quercetin has the potential to reduce bone resorption, but the mechanism by which this compound affects the differentiation of osteoclasts remains unknown. Here, using a bone marrow cell-based in vitro osteoclast differentiation system from bone marrow cells, we found that the ability of quercetin to inhibit osteoclastogenesis was related to its estrogenic activity. The inhibition was partially blocked by a specific antagonist for the nuclear receptor estrogen receptor α, but a specific antagonist of the membrane-type receptor GPR30 completely ablated this inhibition. Furthermore, quercetin suppressed the transient increase of Akt phosphorylation induced by the stimulation of macrophage colony-stimulating factor and receptor activator of NF-κB ligand with no effect on MAPK phosphorylation, suggesting exquisite crosstalk between cytokine receptor and G-protein coupled receptor signaling. These results indicate the important role of GPR30 in osteoclast differentiation and provide new insights to the development of new treatments for osteoporosis.