Risk Factors for Thrombocytopenia Induced by Capecitabine Plus Oxaliplatin Therapy in Patients With Colorectal Cancer.

BACKGROUND/AIM: Capecitabine plus oxaliplatin (CapeOX) therapy is used as an adjuvant chemotherapy regimen for patients with colorectal cancer (CRC). Although oxaliplatin induces thrombocytopenia, the risk factors for thrombocytopenia in oxaliplatin-treated patients with CRC are not well established. We aimed to investigate the risk factors for thrombocytopenia in CapeOX-treated patients with CRC. In addition, we evaluated platelet counts and non-invasive liver fibrosis indices, specifically the aspartate aminotransferase-to-platelet ratio index (APRI) and the fibrosis-4 index (FIB-4), during CapeOX therapy in these patients. PATIENTS AND METHODS: Between July 2017 and June 2020, we enrolled CapeOX-treated patients with high-risk stage II or stage III CRC at seven hospitals collaborating with the Division of Oncology, Aichi Prefectural Society of Hospital Pharmacists (Aichi prefecture, Japan). In this retrospective study, we investigated patients' backgrounds, laboratory data, concomitant medications, number of cycles of CapeOX and oxaliplatin, cumulative dose of oxaliplatin, and administration period. The cut-off values were calculated using receiver operating characteristic analysis of platelet counts and APRI and FIB-4 scores. RESULTS: Fifty-five patients without thrombocytopenia and 44 patients with thrombocytopenia were enrolled. During CapeOX therapy, the thrombocytopenia group showed a significant decrease in platelet count and a significant increase in APRI and FIB-4 scores compared to the non-thrombocytopenia group. Baseline albumin level ≤3.5 g/dl and platelet count ≤238×103/µl were independently associated with ≥grade 2 thrombocytopenia in CapeOX-treated patients. CONCLUSION: Baseline albumin level and platelet count may be useful for predicting thrombocytopenia in CapeOX-treated patients with high-risk stage II or stage III CRC.

Prediction Model for Severe Thrombocytopenia Induced by Gemcitabine Plus Cisplatin Combination Therapy in Patients with Urothelial Cancer.

BACKGROUND: Chemotherapy-induced thrombocytopenia is often a use-limiting adverse reaction to gemcitabine and cisplatin (GC) combination chemotherapy, reducing therapeutic intensity, and, in some cases, requiring platelet transfusion. OBJECTIVE: A retrospective cohort study was conducted on patients with urothelial cancer at the initiation of GC combination therapy and the objective was to develop a prediction model for the incidence of severe thrombocytopenia using machine learning. METHODS: We performed receiver operating characteristic analysis to determine the cut-off values of the associated factors. Multivariate analyses were conducted to identify risk factors associated with the occurrence of severe thrombocytopenia. The prediction model was constructed from an ensemble model and gradient-boosted decision trees to estimate the risk of an outcome using the risk factors associated with the occurrence of severe thrombocytopenia. RESULTS: Of 186 patients included in this study, 46 (25%) experienced severe thrombocytopenia induced by GC therapy. Multivariate analyses revealed that platelet count ≤ 21.4 (×104/µL) [odds ratio 7.19, p < 0.01], hemoglobin ≤ 12.1 (g/dL) [odds ratio 2.41, p = 0.03], lymphocyte count ≤ 1.458 (×103/µL) [odds ratio 2.47, p = 0.02], and dose of gemcitabine ≥ 775.245 (mg/m2) [odds ratio 4.00, p < 0.01] were risk factors of severe thrombocytopenia. The performance of the prediction model using these associated factors was high (area under the curve 0.76, accuracy 0.82, precision 0.68, recall 0.50, and F-measure 0.58). CONCLUSIONS: Platelet count, hemoglobin level, lymphocyte count, and gemcitabine dose contributed to the development of a novel prediction model to identify the incidence of GC-induced severe thrombocytopenia.

Remote follow-up by pharmacists for blood pressure control in patients with hypertension: a systematic review and a meta-analysis of randomized controlled trials.

Hypertension is a major cause of cardiovascular diseases. Several recent studies reported that pharmacists' remote follow-up reduced hypertension patients' blood pressure (BP). This meta-analysis aims to verify whether remote follow-up by pharmacists improves BP levels and reveal the factors that make the intervention effective. The search, conducted using PubMed/Medline, Embase, and Cochrane Library from June to July 2023, targeted articles published between October 1982 and June 2023, using terms including "pharmacist", "hypertension", and "randomized controlled trial (RCT)". The inclusion criteria were: (a) RCTs involving hypertension patients with or without comorbidities, (b) pharmacists using remote communication tools to conduct follow-up encounter during the intervention period, (c) reporting systolic blood pressure (SBP) at baseline and during intervention. SBP was the primary outcome for the meta-analysis. Thirteen studies (3969 participants) were included in this meta-analysis. The mean difference of SBP between intervention group and control group was - 7.35 mmHg (P < 0.0001). Subgroup analyses showed the greater reduction of SBP in the "regularly scheduled follow-up cohort" (- 8.89 mmHg) compared with the "as needed follow-up cohort" (- 3.23 mmHg, P < 0.0001). The results revealed that remote follow-up by pharmacists reduced SBP levels in hypertension patients and scheduled remote follow-up may contribute to the effectiveness.

Development of panorama vision ring for thoracoscopy.

PURPOSE: Minimally invasive surgery (MIS) using a thoraco- or laparoscope is becoming a more common surgical technique. In MIS, a magnified view from a thoracoscope helps surgeons conduct precise operations. However, there is a risk of the visible area becoming narrow. To confirm that the operation field is safe, the surgeon will draw the thoracoscope back to check the marginal area of the target and insert it again many times during MIS. To reduce the surgeon's load, we aim to visualize the entire thoracic cavity using a newly developed device called "panorama vision ring" (PVR). METHOD: The PVR is used instead of a wound retractor or a trocar. It is a ring-type socket with one big hole for the thoracoscope and four small holes for tiny cameras placed around the big hole. The views from the tiny cameras are fused into one wider view that visualizes the entire thoracic cavity. A surgeon can proceed with an operation by checking what exists outside of the thoracoscopic view. Also, she/he can check whether or not bleeding has occurred from the image of the entire cavity. RESULTS: We evaluated the view-expansion ability of the PVR by using a three-dimensional full-scale thoracic model. The experimental results showed that the entire thoracic cavity could be visible in a panoramic view generated by the PVR. We also demonstrated pulmonary lobectomy in virtual MIS using the PVR. Surgeons could perform a pulmonary lobectomy while checking the entire cavity. CONCLUSION: We developed the PVR, which uses tiny auxiliary cameras to create a panoramic view of the entire thoracic cavity during MIS. We aim to make MIS safer for patients and more comfortable for surgeons through the development of the PVR.

Predictive factors for discharge destination after total hip arthroplasty.

BACKGROUND: This study aimed to investigate factors affecting discharge to an inpatient rehabilitation facility or home following total hip arthroplasty, using a clinical pathway in Japan. METHODS: Five hundred hips with osteoarthritis who underwent unilateral total hip arthroplasty at our institution, with no deviation from the pathway, were included in this retrospective study. The variables were examined by univariate analysis. Multivariate logistic regression analysis was used to identify the independent factors that influenced the discharge outcome. RESULTS: Four hundred and thirty-four hips were discharged home directly, and 66 were discharged to an inpatient rehabilitation facility. Patients discharged to an inpatient rehabilitation facility were significantly older, shorter, lighter, and more likely to live alone. Additionally, the preoperative clinical score was significantly lower in the inpatient rehabilitation facility Group for all items. Logistic regression analysis showed a significant association between being discharged to an inpatient rehabilitation facility and higher age [odds ratio 3.87, 95% confidence interval 2.03-7.38, P < 0.001], lower total score in the preoperative Japanese Orthopaedic Association hip score [odds ratio 2.42, 95% confidence interval 1.38-4.23, P = 0.002] and living alone [odds ratio 1.84, 95% confidence interval 1.01-3.35, P = 0.046]. CONCLUSIONS: In this study, age, the preoperative Japanese Orthopaedic Association hip score, and living arrangement impacted the discharge destination after THA.

Establishing a Universal RT-PCR Testing System Is Essential for the Safe Performance of Scheduled Surgeries During the COVID-19 Pandemic in Japan: A Retrospective Study.

Background Elective orthopedic surgery, as well as the procedures of many surgical departments, have been severely curtailed by coronavirus disease 2019. Here, we aimed to analyze how all surgeons could safely perform essential procedures during the coronavirus disease 2019 pandemic. Methods A retrospective review of elective surgeries performed between May 15, 2020, and February 28, 2022, was conducted. A screening questionnaire was used, and reverse transcription-polymerase chain reaction testing was assessed in all admitted surgical department patients. Their positivity rate and the positivity rate in our fever outpatient clinic were analyzed. Results Of 6099 patients who tested for severe acute respiratory syndrome coronavirus-2 during the study period, eight (0.13%) tested positive. The positive results were seen in four patients undergoing orthopedic surgery, two undergoing respiratory surgery, one undergoing breast surgery, and one undergoing plastic surgery. The number of patients who visited the outpatient clinic for fever was 15,639, including 1640 positive cases (positive rate of 10.5%). The positive rate of preoperative reverse transcription-polymerase chain reaction testing for scheduled surgery was consistently low and did not coincide with the peak of the wave of infection, while the positivity rate of outpatients with fever demonstrated a wave consistent with the national infection situation. All 6091 patients, excluding the eight positive patients, underwent surgery; all patients who underwent surgery were discharged from the hospital without developing coronavirus disease 2019 symptoms. Conclusions Our findings suggest that the establishment of a universal reverse transcription-polymerase chain reaction testing system is essential for the safe performance of scheduled surgeries during the coronavirus disease 2019 pandemic.

Articular surface integrity assessed by ultrasound is associated with biological characteristics of articular cartilage in early-stage degeneration.

Early diagnosis of articular cartilage damage and repeated evaluation of treatment efficacy are essential for osteoarthritis treatment. In this study, we established a simple ultrasound grading system for early degenerative articular cartilage and investigated its relationship with cartilage biological characteristics. The ultrasound grading system were based on surface integrity (S1a: continuous high-echo lines, S1b: discontinuous or weak high-echo lines, S2: surface irregular) and cartilage echogenicity (E1: with > 50%, E2: < 50% hypoechoic area of total cartilage layer) and verified by surface roughness (Ra; µm) and histological staining. Ra was lower in S1 than in S2, and the percentage of hypoechoic and safranin O-stained areas was positively correlated. Then we examined its relationship with histopathological evaluation (OARSI grade), gene expression, and protein production in responded to pro-inflammatory cytokine (IL-1ß) stimulation. OARSI grades were different among S grades. The superficial layer of S1 had higher expression of Collagen10, aggrecan, Sox9, and lower expression of Collagen1 and BMP2 than that of S2. S1 responded more pronouncedly to IL-1ß in IL-6, IL-8, and CCL2 production than S2. There was no difference among the E-grades. Taken together, our findings indicate that ultrasound assessment using surface integrity can reflect the biological characteristics of early degenerative articular cartilage.

Meniscus surface texture is associated with degenerative changes in biological and biomechanical properties.

Meniscal degeneration is defined by semi-quantitative assessment of multiple histological findings and has been implicated in biomechanical dysfunction, yet little is known about its relationship with biological properties. This paper aimed to quantitatively evaluate degenerative findings in human meniscus to examine their relationship with gene expression and biomechanical properties, and to extract histological findings that reflect biological properties like gene expression and cytokine secretion. This study included lateral menisci of 29 patients who underwent total knee arthroplasty. The menisci were divided into six samples. For each sample, Pauli's histological evaluation and corresponding quantitative assessment (surface roughness, DNA content, collagen orientation, and GAG content) were performed, with surface roughness showing the highest correlation with the histological evaluation in a single correlation analysis (r = 0.66, p < 0.0001) and multivariate analysis (p < 0.0001). Furthermore, surface roughness was associated with gene expression related to meniscal degeneration and with tangent modulus which decreases with increasing degeneration (r = - 0.49, p = 0.0002). When meniscal tissue was classified by surface integrity, inflammatory cytokine secretion tended to be higher in severe degenerated menisci. These results suggest that the evaluation of meniscal surface texture could predict the degree of degeneration and inflammatory cytokine secretion.

Treatment strategy for surgical site infection post posterior lumbar interbody fusion: A retrospective study.

Introduction: Posterior lumbar interbody fusion (PLIF) has been widely used to treat various degenerative spinal diseases. However, surgical site infection (SSI) post-PLIF is often difficult to cure. This study aimed to clarify the difference in clinical course due to the causative organism and develop a treatment strategy for SSI post-PLIF. Methods: Between January 2011 and March 2019, 581 PLIF surgeries were performed at our hospital. Deep SSI occurred in 14 patients who were followed up for more than 2 years. Causative bacterial species were diagnosed by preoperative puncture and/or intraoperative drainage or by tissue culture in 13 patients and by intradiscal puncture in one patient who underwent conservative treatment. Of the 13 patients who underwent surgeries for infection, 10 had Propionibacterium acnes (Group A; n = 4) or coagulase-negative Staphylococcus (CNS) (Group B; n = 6) as the causative bacterial species. Groups A and B were retrospectively compared in terms of age, sex, number of segments, presence of diabetes mellitus, operation time, blood loss, C-reactive protein on hematological examination, the elapsed time to diagnosis (ETD), the presence of clinical findings such as heat, redness, swelling, and discharge from the wound and healing time. Results: All infections were eradicated with surgery except in one patient whose causative bacteria was CNS; cages were finally removed in 11 patients. There was a significant difference (P = 0.0105) in the ETD and clinical findings (P = 0.0476) between Groups A and B. Posterior one-stage simultaneous revision (POSSR) was performed in nine patients, of whom eight were cured and one required additional surgery. Conclusions: The ETD and clinical findings were significantly different in SSI cases caused by different bacteria, which will be useful in predicting the causative bacteria in future cases. For the treatment of deep SSI post-PLIF, POSSR was effective.

New Strategies for the Treatment of Neuropsychiatric Disorders Based on Reelin Dysfunction.

Reelin is an extracellular matrix protein that is mainly produced in Cajal-Retzius cells and controls neuronal migration, which is important for the proper formation of cortical layers in the developmental stage of the brain. In the adult brain, Reelin plays a crucial role in the regulation of N-methyl-D-aspartate receptor-dependent synaptic function, and its expression decreases postnatally. Clinical studies showed reductions in Reelin protein and mRNA expression levels in patients with psychiatric disorders; however, the causal relationship remains unclear. Reelin-deficient mice exhibit an abnormal neuronal morphology and behavior, while Reelin supplementation ameliorates learning deficits, synaptic dysfunctions, and spine loss in animal models with Reelin deficiency. These findings suggest that the neuronal deficits and brain dysfunctions associated with the down-regulated expression of Reelin are attenuated by enhancements in its expression and functions in the brain. In this review, we summarize findings on the role of Reelin in neuropsychiatric disorders and discuss potential therapeutic approaches for neuropsychiatric disorders associated with Reelin dysfunctions.

Challenges and responses of elective orthopaedic surgery during the second wave of COVID-19.

BACKGROUND: Elective orthopaedic surgery has been severely curtailed because of coronavirus disease, 2019. There is scant scientific evidence to guide surgeons in assessing the protocols that must be implemented before resuming elective orthopaedic surgery safely after the second wave of the coronavirus disease, 2019. METHODS: A retrospective review of elective orthopaedic surgeries performed between May 15, 2020, and November 20, 2020, was conducted. A screening questionnaire was used, and reverse transcription-polymerase chain reaction and severe acute respiratory syndrome coronavirus-2 immunoglobulin G and IgM antibodies testing were assessed in all admitted patients. Screening and testing data for coronavirus disease was reviewed for all patients. RESULTS: Of 592 patients tested for severe acute respiratory syndrome coronavirus-2 during the study period, 21 (3.5%) tested positive. There were 2 patients (0.3%) with positive reverse transcription-polymerase chain reaction tests, 3 (0.5%) with positive IgG and IgM antibodies, 13 (2.2%) with positive IgG antibodies, and 10 (1.7%) with positive IgM antibodies. Among these 21 patients, 20 (95.2%) were asymptomatic. CONCLUSIONS: Our findings suggest that most elective orthopaedic surgery patients with severe acute respiratory syndrome coronavirus-2 are asymptomatic. In the second wave of coronavirus disease, 2019, universal testing of all patients should be strongly considered as an important measure to prevent clusters of in-hospital transmission of the disease.

Alzheimer's Disease Animal Models: Elucidation of Biomarkers and Therapeutic Approaches for Cognitive Impairment.

Alzheimer's disease (AD) is an age-related and progressive neurodegenerative disorder. It is widely accepted that AD is mainly caused by the accumulation of extracellular amyloid ß (Aß) and intracellular neurofibrillary tau tangles. Aß begins to accumulate years before the onset of cognitive impairment, suggesting that the benefit of currently available interventions would be greater if they were initiated in the early phases of AD. To understand the mechanisms of AD pathogenesis, various transgenic mouse models with an accelerated accumulation of Aß and tau tangles have been developed. However, none of these models exhibit all pathologies present in human AD. To overcome these undesirable phenotypes, APP knock-in mice, which were presented with touchscreen-based tasks, were developed to better evaluate the efficacy of candidate therapeutics in mouse models of early-stage AD. This review assesses several AD mouse models from the aspect of biomarkers and cognitive impairment and discusses their potential as tools to provide novel AD therapeutic approaches.

Integrin α2ß1 plays an important role in the interaction between human articular cartilage-derived chondrocytes and atelocollagen gel.

Although atelocollagen gel is used as a scaffold for culturing human articular cartilage-derived chondrocytes, little is known about cell-gel interactions. In this study, we investigated the mechanism via which atelocollagen gel affects human articular cartilage-derived chondrocytes. Two types of three-dimensional cultures of human articular cartilage-derived chondrocytes (i.e., with and without atelocollagen gel) were compared. While the amount of atelocollagen gel in culture gradually decreased with time, it promoted the expression of matrix metalloproteinases (MMPs) during the early stages of culture. Genome-wide differential gene expression analysis revealed that cell membrane- and extracellular matrix-related genes were highly ranked among up- and down-regulated groups in cells cultured in the presence of atelocollagen gel. Among the integrin family of genes, the expression of integrin subunit alpha 2 and integrin subunit alpha 10 was significantly increased in the presence of atelocollagen gel. Blocking α2ß1 integrin with the specific inhibitor BTT 3033 had a significant effect on cell proliferation, MMP expression, and cell shape, as well as on the response to mechanical stimulation. Taken together, our findings indicate that the α2ß1 integrin pathway plays an important role in the interaction of atelocollagen gel with human articular cartilage-derived chondrocytes and may be a potential therapeutic target for articular cartilage disorders.

Improvement of Learning and Memory in Senescence-Accelerated Mice by S-Allylcysteine in Mature Garlic Extract.

S-allylcysteine (SAC), a major thioallyl compound contained in mature garlic extract (MGE), is known to be a neuroactive compound. This study was designed to investigate the effects of SAC on primary cultured hippocampal neurons and cognitively impaired senescence-accelerated mice prone 10 (SAMP10). Treatment of these neurons with MGE or SAC significantly increased the total neurite length and number of dendrites. SAMP10 mice fed MGE or SAC showed a significant improvement in memory dysfunction in pharmacological behavioral analyses. The decrease of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, N-methyl-d-aspartate (NMDA) receptor, and phosphorylated α-calcium/calmodulin-dependent protein kinase II (CaMKII) in the hippocampal tissue of SAMP10 mice fed MGE or SAC was significantly suppressed, especially in the MGE-fed group. These findings suggest that SAC positively contributes to learning and memory formation, having a beneficial effect on brain function. In addition, multiple components (aside from SAC) contained in MGE could be useful for improving cognitive function by acting as neurotrophic factors.

Innate immune activation of astrocytes impairs neurodevelopment via upregulation of follistatin-like 1 and interferon-induced transmembrane protein 3.

BACKGROUND: Polyriboinosinic-polyribocytidylic acid (polyI:C) triggers a strong innate immune response that mimics immune activation by viral infections. Induction of interferon-induced transmembrane protein 3 (Ifitm3) in astrocytes has a crucial role in polyI:C-induced neurodevelopmental abnormalities. Through a quantitative proteomic screen, we previously identified candidate astroglial factors, such as matrix metalloproteinase-3 (Mmp3) and follistatin-like 1 (Fstl1), in polyl:C-induced neurodevelopmental impairment. Here, we characterized the Ifitm3-dependent inflammatory processes focusing on astrocyte-derived Fstl1 following polyI:C treatment to assess the neuropathologic role of Fstl1. METHODS: Astrocytes were treated with PBS (control) or polyI:C (10 µg/mL). The conditioned medium was collected 24 h after the polyI:C treatment and used as astrocyte condition medium (ACM). The expression of Fstl1 mRNA and extracellular Fstl1 protein levels were analyzed by quantitative PCR and western blotting, respectively. For functional studies, neurons were treated with ACM and the effects of ACM on dendritic elongation were assayed. To examine the role of Fstl1, recombinant Fstl1 protein and siRNA for Fstl1 were used. To investigate the expression of Fstl1 in vivo, neonatal mice were treated with vehicle or polyI:C on postnatal day 2 to 6. RESULTS: ACM prepared with polyI:C (polyI:C ACM) contained significantly higher Fstl1 protein than control ACM, but no increase in Fstl1 was observed in polyI:C ACM derived from Ifitm3-deficient astrocytes. We found that the production of Fstl1 involves the inflammatory responsive molecule Ifitm3 in astrocytes and influences neuronal differentiation. In agreement, the levels of Fstl1 increased in the hippocampus of polyI:C-treated neonatal mice. COS7 cells co-transfected with both Fstl1 and Ifitm3 had higher extracellular levels of Fstl1 than the cells transfected with Fstl1 alone. Treatment of primary cultured hippocampal neurons with recombinant Fstl1 impaired dendritic elongation, and the deleterious effect of polyI:C ACM on dendritic elongation was attenuated by knockdown of Fstl1 in astrocytes. CONCLUSIONS: The extracellular level of Fstl1 is regulated by Ifitm3 in astrocytes, which could be involved in polyI:C-induced neurodevelopmental impairment.

Total hip arthroplasty via an anterolateral supine approach for obese patients increases the risk of greater trochanteric fracture.

PURPOSE: The aim of this study was to evaluate the outcomes and early complications of obese patients who underwent total hip arthroplasty for osteoarthritis via an anterolateral approach in the supine position (ALS-THA) and compare these outcome with of a matched control group of non-obese patients. PATIENTS AND METHODS: Thirty-one hips in 28 patients with obesity (BMI ≧ 30 kg/m2) were included in this study. As a control group, 31 hips of 31 patients with a normal weight (BMI between 20 and 25 kg/m2) were matched based on age, sex, and laterality. Clinical evaluations using the Merle d'Aubigne and Postel hip score, radiological evaluations and perioperative complications were compared in two groups. RESULTS: There were no significant differences between the groups in the operative time, period of hospitalization, clinical hip score, or cup positioning, although the position of the cup tended to deviate from the optimal safe zone in the obese compared with non-obese group (32.3 and 16.1%, respectively). There was no infection, dislocation, nerve palsy, or life-threatening event in either group. The rate of avulsion fractures of the greater trochanter in the obese group was 3 times higher compared to that in the non-obese group. CONCLUSIONS: As the clinical outcome of ALS-THA for the obese group is not inferior to that for the non-obese group, obesity is not considered to be a contraindication for ALS-THA. However, obesity increases the risk of intraoperative greater trochanteric fracture. Thus, surgeons should be particularly careful when manipulating the femur in this class of patients, who should be informed of this risk.

Allosteric modulation of the binding affinity between PQBP1 and the spliceosomal protein U5-15kD.

Polyglutamine tract-binding protein 1 (PQBP1) is an intrinsically disordered protein composed of a small folded WW domain and a long disordered region. PQBP1 binds to spliceosomal proteins WBP11 and U5-15kD through its N-terminal WW domain and C-terminal region, respectively. Here, we reveal that the binding between PQBP1 and WBP11 reduces the binding affinity between PQBP1 and U5-15kD. Our results suggest that the interaction between PQBP1 and WBP11 negatively modulates the U5-15kD binding of PQBP1 by an allosteric mechanism.

Girdin phosphorylation is crucial for synaptic plasticity and memory: a potential role in the interaction of BDNF/TrkB/Akt signaling with NMDA receptor.

Synaptic plasticity in hippocampal neurons has been thought to represent a variety of memories. Although accumulating evidence indicates a crucial role of BDNF/TrkB/Akt signaling in the synaptic plasticity of the hippocampus, the mechanism by which Akt, a serine/threonine kinase, controls activity-dependent neuronal plasticity remains unclear. Girdin (also known as APE, GIV, and HkRP1), an actin-binding protein involved both in the remodeling of the actin cytoskeleton and in cell migration, has been identified as a substrate of Akt. Previous studies have demonstrated that deficit of neuronal migration in the hippocampus of Girdin-deficient (Girdin(-/-)) mice is independent on serine phosphorylation of Girdin at S1416 (Girdin S1416) by Akt. In the present study, we focused on the role of Girdin S1416 phosphorylation in BDNF/TrkB/Akt signaling associated with synaptic plasticity. We found that Girdin in the hippocampus was phosphorylated at S1416 in an activity-dependent manner. Phosphorylation-deficient knock-in mice (Girdin(SA/SA) mice), in which S1416 is replaced with alanine, exhibited shrinkage of spines, deficit of hippocampal long-term potentiation, and memory impairment. These phenotypes of Girdin(SA/SA) mice resembled those of Girdin(+/-) mice, which have 50% loss of Girdin expression. Furthermore, Girdin interacted with Src kinase and NR2B subunit of NMDA receptor, leading to phosphorylation of the NR2B subunit and NMDA receptor activation. Our findings suggest that Girdin has two different functions in the hippocampus: Akt-independent neuronal migration and Akt-dependent NR2B phosphorylation through the interaction with Src, which is associated with synaptic plasticity in the hippocampus underlying memory formation.

Alterations of GABAergic and dopaminergic systems in mutant mice with disruption of exons 2 and 3 of the Disc1 gene.

Disrupted-in-schizophrenia-1 (DISC1) has been widely associated with several psychiatric disorders, including schizophrenia, mood disorders and autism. We previously reported that a deficiency of DISC1 may induce low anxiety and/or high impulsivity in mice with disruption of exons 2 and 3 of the Disc1 gene (Disc1(Δ2-3/Δ2-3)). It remains unclear, however, if deficiency of DISC1 leads to specific alterations in distinct neuronal systems. In the present study, to understand the role of DISC1 in γ-aminobutyric acid (GABA) interneurons and mesocorticolimbic dopaminergic (DAergic) neurons, we investigated the number of parvalbumin (PV)-positive interneurons, methamphetamine (METH)-induced DA release and the expression levels of GABAA, DA transporter (DAT) and DA receptors in wild-type (Disc1(+/+)) and Disc1(Δ2-3/Δ2-3) mice. Female Disc1(Δ2-3/Δ2-3) mice showed a significant reduction of PV-positive interneurons in the hippocampus, while no apparent changes were observed in mRNA expression levels of GABAA receptor subunits. METH-induced DA release was significantly potentiated in the nucleus accumbens (NAc) of female Disc1(Δ2-3/Δ2-3) mice, although there were no significant differences in the expression levels of DAT. Furthermore, the expression levels of DA receptor mRNA were upregulated in the NAc of female Disc1(Δ2-3/Δ2-3) mice. Male Disc1(Δ2-3/Δ2-3) mice showed no apparent differences in all experiments. DISC1 may play a critical role in gender-specific developmental alteration in GABAergic inhibitory interneurons and DAergic neurons.