Biology subjects

Tabuchi, K.

Publications and source records attributed to Tabuchi, K..

4 recordsLinked to original sources

bioRxiv2021

Systematic analysis of brain lactate and pH levels in 65 animal models related to neuropsychiatric conditions

Increased levels of lactate, an end-product of glycolysis, have been proposed as a potential surrogate marker for metabolic changes during neuronal excitation. These changes in lactate levels can result in decreased brain pH, which has been implicated in patients with various neuropsychiatric disorders. We previously demonstrated that such alterations are commonly observed in five mouse models of schizophrenia, bipolar disorder, and autism, suggesting a shared endophenotype among these disorders rather than mere artifacts due to medications or agonal state. However, there is still limited research on this phenomenon in animal models, leaving its generality across other disease animal models uncertain. Moreover, the association between changes in brain lactate levels and specific behavioral abnormalities remains unclear. To address these gaps, the International Brain pH Project Consortium investigated brain pH and lactate levels in 109 strains/conditions of 2,294 animals with genetic and other experimental manipulations relevant to neuropsychiatric disorders. Systematic analysis revealed that decreased brain pH and increased lactate levels were common features observed in multiple models of depression, epilepsy, Alzheimers disease, and some additional schizophrenia models. While certain autism models also exhibited decreased pH and increased lactate levels, others showed the opposite pattern, potentially reflecting subpopulations within the autism spectrum. Furthermore, utilizing large-scale behavioral test battery, a multivariate cross-validated prediction analysis demonstrated that poor working memory performance was predominantly associated with increased brain lactate levels. Importantly, this association was confirmed in an independent cohort of animal models. Collectively, these findings suggest that altered brain pH and lactate levels, which could be attributed to dysregulated excitation/inhibition balance, may serve as transdiagnostic endophenotypes of debilitating neuropsychiatric disorders characterized by cognitive impairment, irrespective of their beneficial or detrimental nature.

neuroscience↗

bioRxiv2020

Neurexins play a crucial role in cerebellar granule cell survival by organizing autocrine machinery for neurotrophins

Neurexins (NRXNs) are among the key presynaptic cell adhesion molecules that regulate synapse function and formation via trans-synaptic interaction with postsynaptic ligands. Here, we generated cerebellar granule cell (CGC)-specific Nrxn triple-knockout (TKO) mice to allow the deletion of all NRXNs. Unexpectedly, most CGCs died in these mice. The requirement of NRNXs for cell survival was reproduced in cultured CGCs. We showed that the axons of cultured Nrxn TKO CGCs that were not in contact with the postsynaptic structure had defects in the formation of presynaptic protein cluster and action potential-induced Ca2+ influx. Additionally, these cells were impaired in the secretion from axons of depolarization-induced fluorescence-tagged brain-derived neurotrophic factor (BDNF), and the cell-survival defect was rescued by the application of BDNF. Our results suggest that CGC survival is maintained by autocrine neurotrophic factors, and that NRXNs organize the presynaptic protein clusters and the autocrine neurotrophic factor secretory machinery independent of contact with postsynaptic ligands.

neuroscience↗

bioRxiv2019

IQSEC3 Mediates Npas4-dependent GABAergic Synaptic Transmission and Depressive-like Behavior

Organization of mammalian inhibitory synapses is thought to be crucial for normal brain functions, but the underlying molecular mechanisms have been still incompletely understood. IQSEC3 (IQ motif and Sec7 domain 3) is a guanine nucleotide exchange factor for ADP-ribosylation factor (ARF-GEF) that directly interacts with gephyrin. Here, we show that GABAergic synapse-specific transcription factor, Npas4 (neuronal PAS domain protein 4) directly binds to the promoter of Iqsec3 and regulates its transcription. Strikingly, an enriched environment (EE) induced Npas4 upregulation and concurrently increased IQSEC3 protein levels specifically in mouse CA1 stratum oriens layer somatostatin (SST)-expressing GABAergic interneurons, which are compromised in Npas4-knockout (KO) mice. Moreover, expression of wild-type (WT) IQSEC3, but not a dominant-negative (DN) ARF-GEF-inactive mutant, rescued the decreased GABAergic synaptic transmission in Npas4-deficient SST interneurons. Concurrently, expression of IQSEC3 WT normalized the altered GABAergic synaptic transmission in dendrites, but not soma, of Npas4-deficient CA1 pyramidal neurons. Furthermore, expression of IQSEC3 WT, but not IQSEC3 DN, in SST-expressing interneurons in CA1 SST Npas4-KO mice rescued the altered anxiety-like behavior. Collectively, our results suggest that IQSEC3 is a key GABAergic synapse component that is directed by Npas4 activity- and ARF activity-dependent gene programs in SST-expressing interneurons to orchestrate the functional excitation-to-inhibition balance.

neuroscience↗

bioRxiv2019

Toward Health Management of Major Labour Force Generation by Using Infection Control Countermeasures for Haematobium Schistosomiasis -assumed to be related to occupational risk- in the Republic of Malawi

BackgroundIn Malawi, haematobium schistosomiasis is highly endemic. According to previous studies, countermeasures have been conducted mainly in school-aged children. In this study, we focused on the age groups, which are assumed to be major labour force generation. Haematobium schistosomiasis is supposed to be related to occupational activities in schistosome endemic countries. MethodsWe chronologically followed the transition of schistosome egg positive prevalence before and after mass drug administration of praziquantel (MDA) by using a urine filtering examination. We also analyzed the effectiveness of urine reagent strips from the cost perspective. FindingsThe egg positive prevalence was 34.3% (95%CI: 28.5-40.5) just before MDA in June 2010 and the highest prevalence was in the age of twenties. The egg positive prevalence reduced to 12.7% (95%CI: 9.2-17.3, p<0.01) eight weeks after the first MDA and the prevalence reduced to 6.9% (95%CI: 4.6-10.0, p<0.01) after the second MDA in August 2011. The egg positive prevalence after MDA in 2013 was reduced from 3.8% (95%CI: 2.1-6.9) to 0.9% (95%CI: 0.3-3.4) and p value was 0.050. Using urine reagent strips after MDA, the positive predictive value decreased, but the negative predictive value remained high. The cost of one urine reagent strip and one tablet of praziquantel were US$0.06 and US$0.125 in 2013 in Malawi. If the egg positive prevalence is 40%, screening subjects for MDA using urine reagent strips, the cost reduction can be estimated to be about 24% -showing an overall cost reduction. ConclusionThe combination of MDA and urine reagent strips could be both a practical and cost-effective countermeasure for haematobium schistosomiasis. It is key to recognize that haematobium schistosomiasis could be considered a disease that is assumed to have some concern with occupational risk in tropical agricultural countries such as Malawi. From this point of view, it is very important to protect the health of workers; the sound labour force generation is vital for economic growth and development in these countries. Author summarySchistosomiasis is widely endemic in the tropical and subtropical countries including Malawi, and it is related that more than 300 million people suffer from associated severe morbidity. The pathway of transmission is mainly contacting infested fresh water and it is inevitable to contact fresh water through their daily activities in Malawi. Then, they are routinely exposed to the risk of schistosome infection. Previously the main targets of schistosome control were school-aged children, but our research showed main population of schistosome infection was twenties that was presumed to be major labour force. Agriculture is the dominant industry in Malawi and it can be related to be at risk of schistosome infection during agricultural work. Schistosomiasis is presumed to have occupation-related risks, we consider that schistosome control will be a valuable step-up to economic development and make a social contribution in Malawi and many low-income tropical countries. FundingThe Ministry of Education, Culture, Sports, Science and Technology of Japans scientific research grant (JSPS KAKENHI Grant Number JP23406025). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

microbiology↗