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Animal adaptation to environmental goals to pursue rewards is modulated by dopamine. However, the role of dopamine in the hippocampus, involved in spatial navigation, remains unclear. Here, we studied dopaminergic inputs from the ventral tegmental area (VTA) to the hippocampus, focusing on spatial goal persistence and adaptation. Mice with VTA dopaminergic lesions struggled to locate and update learned reward locations in a circular maze with dynamic reward locations, emphasizing the importance of VTA dopaminergic neurons in the persistence and adaptation of spatial memory. Further, these deficits were accompanied by motor impairments or motivational loss even when dopamine receptors in the dorsal hippocampus were selectively blocked. Stimulation of VTA dopaminergic axons within the dorsal hippocampus enhanced the mice's ability to adapt to changing reward locations. These findings provide insights into the contribution of dopaminergic inputs within the hippocampus to spatial goal adaptation.
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Several maze shapes are used to test spatial navigation performance and behavioral phenotypes. Traditionally, each experiment requires a unique maze shape, thus requiring several separate mazes in different configurations. The maze geometry cannot be reconfigured in a single environment to accommodate scalability and reproducibility. The reconfigurable maze is a unique approach to address the limitations, allowing quick and flexible configurations of maze pathways in a repeatable manner. It consists of interlocking pathways and includes feeders, treadmills, movable walls, and shut-off sensors. The current protocol describes how the reconfigurable maze can replicate existing mazes, including the T-shaped, plus-shaped, W-shaped, and figure-eight mazes. Initially, the T-shaped maze was constructed inside a single experimental room, followed by modifications. The rapid and scalable protocol outlined herein demonstrates the flexibility of the reconfigurable maze, achieved through the addition of components and behavioral training phases in a stepwise manner. The reconfigurable maze systematically and precisely assesses the performance of multiple aspects of spatial navigation behavior.
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Navegación Espacial , Animales , Aprendizaje por Laberinto , Roedores , Reproducibilidad de los Resultados , Conducta EspacialRESUMEN
The superior longitudinal fasciculus (SLF) is a white matter structure that has long bidirectional projections among the prefrontal, temporal, occipital, and parietal cortices and extends over a wide area in a human brain. Recently, anatomical details of the SLF have been clarified using a diffusion tensor imaging (DTI) template of subjects from the Human Connectome Project. However, the neurobehavioral functions of the SLF have not been fully elucidated. It is speculated that the SLF contributes to a broad cognitive domain including visuospatial nonverbal cognitive ability and verbal memory ability because of its anatomical location; however, previous findings in imaging studies are inconsistent. Showing the contribution of the SLF to cognitive function may be important for improving our understanding of the functional role of white matter structures in the human brain. This study aimed to identify the relationship between DTI indices of the SLF and the Verbal Comprehension, Perceptual Organization, Working Memory and Processing Speed Indices of the Wechsler Adult Intelligence Scale-Third Edition using regression analysis, accounting for the effects of age, sex and scanner type in 583 healthy volunteers. We showed significant correlations between the fractional anisotropy of the left SLF and the Perceptual Organization Index (ßâ¯=â¯0.21, pâ¯=⯠4.5×10-4) and Working Memory Index (ßâ¯=â¯0.19, pâ¯=⯠4.0×10-4). These findings may have implications for the rehabilitation of cognitive function in patients with neurological disorders.
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Cognición/fisiología , Memoria a Corto Plazo/fisiología , Tiempo de Reacción/fisiología , Sustancia Blanca/diagnóstico por imagen , Adolescente , Adulto , Anciano , Imagen de Difusión Tensora , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Vías Nerviosas/diagnóstico por imagen , Pruebas Neuropsicológicas , Sustancia Blanca/fisiología , Adulto JovenRESUMEN
Previous studies have indicated associations between several OLIG2 gene single-nucleotide polymorphisms (SNPs) and susceptibility to schizophrenia among Caucasians. Consistent with these findings, postmortem brain and diffusion tensor imaging studies have indicated that the schizophrenia-risk-associated allele (A) in the OLIG2 SNP rs1059004 predicts lower OLIG2 gene expression in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia patients and reduced white matter (WM) integrity of the corona radiata in normal brains among Caucasians. In an effort to replicate the association between this variant and WM integrity among healthy Japanese, we found that the number of A alleles was positively correlated with WM integrity in some fiber tracts, including the right posterior limb of the internal capsule, and with mean blood flow in a widespread area, including the inferior frontal operculum, orbital area, and triangular gyrus. Because the A allele affected WM integrity in opposite directions in Japanese and Caucasians, we investigated a possible association between the OLIG2 gene SNPs and the expression level of OLIG2 transcripts in postmortem DLPFCs. We evaluated rs1059004 and additional SNPs in the 5' upstream and 3' downstream regions of rs1059004 to cover the broader region of the OLIG2 gene. The 2 SNPs (rs1059004 and rs9653711) had opposite effects on OLIG2 gene expression in the DLPFC in Japanese and Caucasians. These findings suggest ethnicity-dependent opposite effects of OLIG2 gene SNPs on WM integrity and OLIG2 gene expression in the brain, which may partially explain the failures in replicating associations between genetic variants and psychiatric phenotypes among ethnicities.
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Pueblo Asiatico , Cápsula Interna/patología , Factor de Transcripción 2 de los Oligodendrocitos/genética , Corteza Prefrontal/metabolismo , Esquizofrenia , Sustancia Blanca/patología , Población Blanca , Adulto , Pueblo Asiatico/etnología , Pueblo Asiatico/genética , Diagnóstico , Imagen de Difusión Tensora , Expresión Génica/genética , Predisposición Genética a la Enfermedad , Humanos , Cápsula Interna/diagnóstico por imagen , Polimorfismo de Nucleótido Simple , Esquizofrenia/diagnóstico por imagen , Esquizofrenia/etnología , Esquizofrenia/genética , Esquizofrenia/patología , Sustancia Blanca/diagnóstico por imagen , Población Blanca/etnología , Población Blanca/genéticaRESUMEN
AIM: Matrix metalloproteinase-9 (MMP-9) has been shown to modulate synaptic plasticity and may contribute to the pathophysiology of schizophrenia. This study investigated the peripheral levels of MMP-9 and its association with cognitive functions in patients with schizophrenia to see the possible involvement of MMP-9 in pathophysiology of schizophrenia, especially in cognitive decline. METHODS: We measured the plasma levels of MMP-9 in 257 healthy controls and 249 patients with schizophrenia, including antipsychotic drug-free patients. We also explored the possible association between plasma MMP-9 levels and cognitive performance in healthy controls and patients with schizophrenia using the Wechsler Adult Intelligence Scale, Third Edition (WAIS- III), the Wechsler Memory Scale-Revised (WMS-R), and the Rey Auditory Verbal Learning Test (AVLT). RESULTS: We found that the plasma levels of MMP-9 were significantly higher in patients with schizophrenia, including antipsychotic drug-free patients, than in healthy controls. We found a significant negative association between plasma MMP-9 levels and cognitive performance in controls and patients with schizophrenia. CONCLUSION: Together, these convergent data suggest a possible biological mechanism for schizophrenia, whereby increased MMP-9 levels are associated with cognitive impairment.
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Cognición/fisiología , Metaloproteinasa 9 de la Matriz/sangre , Esquizofrenia/sangre , Esquizofrenia/diagnóstico , Psicología del Esquizofrénico , Adulto , Antipsicóticos/farmacología , Antipsicóticos/uso terapéutico , Biomarcadores/sangre , Cognición/efectos de los fármacos , Estudios de Cohortes , Femenino , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Esquizofrenia/tratamiento farmacológicoRESUMEN
Multiple mazes are routinely used to test the performance of animals because each has disadvantages inherent to its shape. However, the maze shape cannot be flexibly and rapidly reproduced in a repeatable and scalable way in a single environment. Here, to overcome the lack of flexibility, scalability, reproducibility, and repeatability, we develop a reconfigurable maze system that consists of interlocking runways and an array of accompanying parts. It allows experimenters to rapidly and flexibly configure a variety of maze structures along the grid pattern in a repeatable and scalable manner. Spatial navigational behavior and hippocampal place coding were not impaired by the interlocking mechanism. As a proof-of-principle demonstration, we demonstrate that the maze morphing induces location remapping of the spatial receptive field. The reconfigurable maze thus provides flexibility, scalability, repeatability, and reproducibility, therefore facilitating consistent investigation into the neuronal substrates for learning and memory and allowing screening for behavioral phenotypes.
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AIM: Neuroimaging studies have revealed that patients with schizophrenia exhibit reduced gray matter volume in various regions. With these findings, various studies have indicated that structural MRI can be useful for the diagnosis of schizophrenia. However, multisite studies are limited. Here, we evaluated a simple model that could be used to differentiate schizophrenia from control subjects considering MRI scanner differences employing voxel-based morphometry. METHODS: Subjects were 541 patients with schizophrenia and 1252 healthy volunteers. Among them, 95 patients and 95 controls (Dataset A) were used for the generation of regions of interest (ROI), and the rest (Dataset B) were used to evaluate our method. The two datasets were comprised of different subjects. Three-dimensional T1-weighted MRI scans were taken for all subjects and gray-matter images were extracted. To differentiate schizophrenia, we generated ROI for schizophrenia from Dataset A. Then, we determined volume within the ROI for each subject from Dataset B. Using the extracted volume data, we calculated a differentiation feature considering age, sex, and intracranial volume for each MRI scanner. Receiver-operator curve analyses were performed to evaluate the differentiation feature. RESULTS: The area under the curve ranged from 0.74 to 0.84, with accuracy from 69% to 76%. Receiver-operator curve analysis with all samples revealed an area under the curve of 0.76 and an accuracy of 73%. CONCLUSION: We moderately successfully differentiated schizophrenia from control using structural MRI from differing scanners from multiple sites. This could be useful for applying neuroimaging techniques to clinical settings for the accurate diagnosis of schizophrenia.
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Sustancia Gris/diagnóstico por imagen , Neuroimagen/métodos , Neuroimagen/normas , Esquizofrenia/diagnóstico por imagen , Adulto , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Adulto JovenRESUMEN
Identifying both the commonalities and differences in brain structures among psychiatric disorders is important for understanding the pathophysiology. Recently, the ENIGMA-Schizophrenia DTI Working Group performed a large-scale meta-analysis and reported widespread white matter microstructural alterations in schizophrenia; however, no similar cross-disorder study has been carried out to date. Here, we conducted mega-analyses comparing white matter microstructural differences between healthy comparison subjects (HCS; N = 1506) and patients with schizophrenia (N = 696), bipolar disorder (N = 211), autism spectrum disorder (N = 126), or major depressive disorder (N = 398; total N = 2937 from 12 sites). In comparison with HCS, we found that schizophrenia, bipolar disorder, and autism spectrum disorder share similar white matter microstructural differences in the body of the corpus callosum; schizophrenia and bipolar disorder featured comparable changes in the limbic system, such as the fornix and cingulum. By comparison, alterations in tracts connecting neocortical areas, such as the uncinate fasciculus, were observed only in schizophrenia. No significant difference was found in major depressive disorder. In a direct comparison between schizophrenia and bipolar disorder, there were no significant differences. Significant differences between schizophrenia/bipolar disorder and major depressive disorder were found in the limbic system, which were similar to the differences in schizophrenia and bipolar disorder relative to HCS. While schizophrenia and bipolar disorder may have similar pathological characteristics, the biological characteristics of major depressive disorder may be close to those of HCS. Our findings provide insights into nosology and encourage further investigations of shared and unique pathophysiology of psychiatric disorders.
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Encéfalo/patología , Trastornos Mentales/patología , Sustancia Blanca/patología , Adulto , Trastorno del Espectro Autista/fisiopatología , Trastorno Bipolar/fisiopatología , Encéfalo/metabolismo , Trastorno Depresivo Mayor/fisiopatología , Imagen de Difusión Tensora/métodos , Femenino , Humanos , Masculino , Trastornos Mentales/metabolismo , Persona de Mediana Edad , Esquizofrenia/fisiopatología , Sustancia Blanca/metabolismoRESUMEN
AIM: Previous studies have reported different brain morphologies in different cognitive subgroups of patients with schizophrenia. We aimed to examine the brain structures and functional connectivity in these cognitive subgroups of schizophrenia. METHODS: We compared brain structures among healthy controls and cognitively deteriorated and preserved subgroups of patients with schizophrenia according to the decline in IQ. Connectivity analyses between subcortical regions and other brain areas were performed using resting-state functional magnetic resonance imaging among the groups. RESULTS: Whole brain and total cortical gray matter, right fusiform gyrus, left pars orbitalis gyrus, right pars triangularis, left superior temporal gyrus and left insula volumes, and bilateral cortical thickness were decreased in the deteriorated group compared to the control and preserved groups. Both schizophrenia subgroups had increased left lateral ventricle, right putamen and left pallidum, and decreased bilateral hippocampus, left precentral gyrus, right rostral middle frontal gyrus, and bilateral superior frontal gyrus volumes compared with controls. Hyperconnectivity between the thalamus and a broad range of brain regions was observed in the deteriorated group compared to connectivity in the control group, and this hyperconnectivity was less evident in the preserved group. We also found hyperconnectivity between the accumbens and the superior and middle frontal gyri in the preserved group compared with connectivity in the deteriorated group. CONCLUSION: These findings provide evidence of prominent structural and functional brain abnormalities in deteriorated patients with schizophrenia, suggesting that cognitive subgroups in schizophrenia might be useful biotypes to elucidate brain pathophysiology for new diagnostic and treatment strategies.
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Corteza Cerebral , Disfunción Cognitiva , Conectoma , Cuerpo Estriado , Sustancia Gris , Esquizofrenia , Adulto , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/etiología , Disfunción Cognitiva/patología , Disfunción Cognitiva/fisiopatología , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/patología , Cuerpo Estriado/fisiopatología , Femenino , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Sustancia Gris/fisiopatología , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Hipocampo/fisiopatología , Humanos , Inteligencia/fisiología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esquizofrenia/complicaciones , Esquizofrenia/diagnóstico por imagen , Esquizofrenia/patología , Esquizofrenia/fisiopatología , Adulto JovenRESUMEN
The Fawn-Hooded (FH) rat carries a gene mutation that results in a dysfunctional serotoninergic system. However, previous studies have reported differing features between the FH/Wjd and FH/Har strains. We aimed to compare the behavioural and neurobiological features of FH/HamSlc rats with those of Fischer 344 rats. We performed the open field, elevated minus-maze, Y-maze spontaneous alternation, and forced swim tests to investigate behavioural alterations. We also assessed neurobiological characteristics by quantifying monoamines and their related compounds in the prefrontal cortex, hippocampus, and striatum using high-performance liquid chromatography with an electrochemical detection system. FH/HamSlc rats showed hyperactivity and a high impulsivity tendency in the open field and the elevated minus maze test, but no cognitive dysfunction. In addition, the hyperactivity was suppressed immediately after the forced swim test. FH/HamSlc rats showed low dopamine levels, but high dopamine turnover in the striatum. Serotonin and noradrenaline levels were low in the prefrontal cortex and the hippocampus of FH/HamSlc rats, but high serotonin turnover was observed in the prefrontal cortex, hippocampus, and striatum. FH/HamSlc rats show (1) mania-like behavioural characteristics that are different from those of other strains of FH rats; (2) stimulus dependent suppression of hyperactivity similar to the clinical findings that exercise alleviates the symptoms of bipolar disorder; and (3) monoaminergic dysregulation such as monoamine imbalance and hyperturnover that may be associated with mania-related behavioural characteristics. Thus, the FH/HamSlc rat is a new animal model for mania including bipolar disorder.
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BACKGROUND: Eye movement abnormalities have been identified in schizophrenia; however, their relevance to cognition is still unknown. In this study, we explored the general relationship between eye movements and cognitive function. METHODS: The three eye movement measures (scanpath length, horizontal position gain, and duration of fixations) that were previously reported to be useful in distinguishing subjects with schizophrenia from healthy subjects, as well as Wechsler Adult Intelligence Scale-III (WAIS-III) scores, were collected and tested for association in 113 subjects with schizophrenia and 404 healthy subjects. RESULTS: Scanpath length was positively correlated with matrix reasoning and digit symbol coding in subjects with schizophrenia and correlated with vocabulary and symbol search in healthy subjects. Upon testing for interaction effects of diagnosis and scanpath length on correlated WAIS-III scores, a significant interaction effect was only observed for matrix reasoning. The positive correlation between scanpath length and matrix reasoning, which was specific to subjects with schizophrenia, remained significant after controlling for demographic confounders such as medication and negative symptoms. No correlation was observed between the two other eye movement measures and any of the WAIS-III scores. CONCLUSIONS: Herein, we reveal novel findings on the association between eye-movement-based measures of visual exploration and cognitive scores requiring visual search in subjects with schizophrenia and in healthy subjects. The association between scanpath length and matrix reasoning, a measure of perceptual organization in subjects with schizophrenia, implies the existence of common cognitive processes, and subjects with longer scanpath length may be advantageous in performance of perceptual organization tasks.
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Disfunción Cognitiva/fisiopatología , Trastornos de la Motilidad Ocular/fisiopatología , Trastornos de la Percepción/fisiopatología , Esquizofrenia/fisiopatología , Percepción Visual/fisiología , Adulto , Disfunción Cognitiva/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos de la Motilidad Ocular/etiología , Trastornos de la Percepción/etiología , Esquizofrenia/complicacionesRESUMEN
BACKGROUND: Patients with schizophrenia show various trajectories in intelligence. However, whether the degree of IQ decline is associated with functional outcomes remains unclear. The purposes of the study were 1) to determine whether IQ decline was related with work outcome, and 2) to perform predictions for attaining a certain amount of work measured by work hours. METHODS: One hundred and forty patients with schizophrenia and 156 healthy volunteers enrolled in the study. The patients were classified into the deteriorated group or preserved group based on the degree of IQ decline. In addition to current and premorbid intelligence, functional outcomes and clinical conditions were also evaluated. Those variables were compared among the patient groups and healthy adults to select independent variables for logistic regression analyses. Four separate logistic regression analyses were conducted with work hours dichotomized by four criteria (0, 10, 20, or 30â¯h per week) as dependent variables. RESULTS: IQ decline remained significant in all regression models except the model with the 30â¯h per week criterion. Social function and psychiatric symptoms were also prominent factors in most models. Predictions were more accurate in the models with higher criteria. Individual probabilities to exceed each criterion were presented based on the equations derived from the regression models. CONCLUSION: Intellectual deterioration, in addition to impaired social function and psychiatric symptoms, may play a key role in work disturbances in patients with schizophrenia. Probability models presented here have strengths in evaluating the ability to work from statistical, clinical, and theoretical viewpoints.
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Empleo/psicología , Inteligencia , Esquizofrenia/diagnóstico , Psicología del Esquizofrénico , Adulto , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Modelos Estadísticos , Probabilidad , PronósticoRESUMEN
Patients with schizophrenia show severe impairment in social function and have difficulty in their daily social life. Although a recent large-scale multicenter study revealed alterations in white matter microstructures, the association between these anatomical changes and social dysfunction in schizophrenia remains unknown. Therefore, we investigated the association between the white matter integrity of regions of interest and social function in schizophrenia. A total of 149 patients with schizophrenia and 602 healthy comparison subjects (HCS) underwent DTI and completed the Picture Arrangement subtest of the Wechsler Adult Intelligence Scale-Third Edition and the Finance subscale of the University of California, San Diego, Performance-Based Skills Assessment Brief, as social indices of interest. The fractional anisotropy (FA) in the anterior corona radiata and corpus callosum was significantly lower in patients than in HCS, and the radial diffusivity (RD) in the anterior corona radiata and corpus callosum was significantly higher in patients. The Picture Arrangement and Finance scores were both significantly impaired in patients. The effect of the FA of the right anterior corona radiata on the Finance score and the Picture Arrangement score, of the RD of the right anterior corona radiata on the Picture Arrangement score, and of the RD of the corpus callosum on the Picture Arrangement score were significant. In conclusion, our results confirmed the association between structural connectivity in the right frontal white matter and corpus callosum and social function in schizophrenia. These findings may provide a foundation for developing an intervention for functional recovery in schizophrenia.
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Cuerpo Calloso/diagnóstico por imagen , Esquizofrenia/diagnóstico por imagen , Psicología del Esquizofrénico , Conducta Social , Sustancia Blanca/diagnóstico por imagen , Adolescente , Adulto , Anciano , Imagen de Difusión Tensora , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Adulto JovenRESUMEN
Background: An imbalance in the inflammatory tumor necrosis factor system, including soluble tumor necrosis factor receptor 2 (sTNFR2), may contribute to the pathophysiology of schizophrenia. Methods: We measured the plasma levels of sTNFR2 in 256 healthy controls and 250 patients with schizophrenia including antipsychotic drug-free patients and treatment-resistant patients. We also explored the possible association between plasma sTNFR2 levels and cognitive performance in healthy controls and patients with schizophrenia using the Wechsler Adult Intelligence Scale, Third Edition, the Wechsler Memory Scale-Revised, and the Rey Auditory Verbal Learning Test. An association between plasma sTNFR2 levels and hippocampal volume in controls and patients with schizophrenia was also investigated via MRI. Results: We found that the plasma levels of sTNFR2 were significantly higher in patients with schizophrenia, including both antipsychotic drug-free patients and treatment-resistant patients. We found a significant negative association between plasma sTNFR2 levels and cognitive performance in controls and patients with schizophrenia. Hippocampal volume was also negatively associated with plasma sTNFR2 levels in patients with schizophrenia. Conclusion: Together, these convergent data suggest a possible biological mechanism for schizophrenia, whereby increased sTNFR2 levels are associated with a smaller hippocampal volume and cognitive impairment.
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Disfunción Cognitiva/fisiopatología , Hipocampo/patología , Receptores Tipo II del Factor de Necrosis Tumoral/sangre , Esquizofrenia/sangre , Esquizofrenia/patología , Esquizofrenia/fisiopatología , Adulto , Anciano , Disfunción Cognitiva/etiología , Femenino , Hipocampo/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esquizofrenia/complicacionesRESUMEN
The number of AMPA-type glutamate receptors (AMPARs) at synapses is the major determinant of synaptic strength and varies from synapse to synapse. To clarify the underlying molecular mechanisms, the density of AMPARs, PSD-95, and transmembrane AMPAR regulatory proteins (TARPs) were compared at Schaffer collateral/commissural (SCC) synapses in the adult mouse hippocampal CA1 by quantitative immunogold electron microscopy using serial sections. We examined four types of SCC synapses: perforated and nonperforated synapses on pyramidal cells and axodendritic synapses on parvalbumin-positive (PV synapse) and pravalbumin-negative interneurons (non-PV synapse). SCC synapses were categorized into those expressing high-density (perforated and PV synapses) or low-density (nonperforated and non-PV synapses) AMPARs. Although the density of PSD-95 labeling was fairly constant, the density and composition of TARP isoforms was highly variable depending on the synapse type. Of the three TARPs expressed in hippocampal neurons, the disparity in TARP γ-2 labeling was closely related to that of AMPAR labeling. Importantly, AMPAR density was significantly reduced at perforated and PV synapses in TARP γ-2-knock-out (KO) mice, resulting in a virtual loss of AMPAR disparity among SCC synapses. In comparison, TARP γ-8 was the only TARP expressed at nonperforated synapses, where AMPAR labeling further decreased to a background level in TARP γ-8-KO mice. These results show that synaptic inclusion of TARP γ-2 potently increases AMPAR expression and transforms low-density synapses into high-density ones, whereas TARP γ-8 is essential for low-density or basal expression of AMPARs at nonperforated synapses. Therefore, these TARPs are critically involved in AMPAR density control at SCC synapses. SIGNIFICANCE STATEMENT: Although converging evidence implicates the importance of transmembrane AMPA-type glutamate receptor (AMPAR) regulatory proteins (TARPs) in AMPAR stabilization during basal transmission and synaptic plasticity, how they control large disparities in AMPAR numbers or densities across central synapses remains largely unknown. We compared the density of AMPARs with that of TARPs among four types of Schaffer collateral/commissural (SCC) hippocampal synapses in wild-type and TARP-knock-out mice. We show that the density of AMPARs correlates with that of TARP γ-2 across SCC synapses and its high expression is linked to high-density AMPAR expression at perforated type of pyramidal cell synapses and synapses on parvalbumin-positive interneurons. In comparison, TARP γ-8 is the only TARP expressed at nonperforated type of pyramidal cell synapses, playing an essential role in low-density or basal AMPAR expression.
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Región CA1 Hipocampal/fisiología , Canales de Calcio/fisiología , Receptores AMPA/metabolismo , Sinapsis/fisiología , Animales , Canales de Calcio/genética , Homólogo 4 de la Proteína Discs Large , Potenciales Postsinápticos Excitadores , Guanilato-Quinasas/biosíntesis , Guanilato-Quinasas/genética , Masculino , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Piramidales/fisiología , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Transmisión SinápticaRESUMEN
PURPOSE: Serotonin, a neurotransmitter synthesized from tryptophan, has been proposed to play a key role in central fatigue. In this study, we examined whether tryptophan itself and/or its two metabolites, kyneurenic acid (KYNA) and quinolinic acid (QUIN), are involved in central fatigue. MATERIALS AND METHODS: Experiments were conducted using Sprague-Dawley rats (SDR) and Nagase analbuminemic rats (NAR). Central fatigue was assessed by treadmill running and a Morris water maze test. Microdialysis was used to collect samples for measurement of extracellular concentration of tryptophan, serotonin and 5-hydroxyindoleacetic acid (5-HIAA) and to infuse test agents. To examine the kinetics of release, synaptosomes in the striatum were prepared in vitro to measure intra- and extrasynaptosomal concentration of tryptophan, serotonin and 5-HIAA. RESULTS: The concentration of tryptophan secreted into the extracellular space of the striatum was higher during fatigue only, and quickly returned to basal levels with recovery from fatigue. Running time to exhaustion was reduced by activation of tryptophan receptors. Time to exhaustion was shorter in NAR, which maintain a higher extracellular level of striatum tryptophan than SDR. Impaired memory performance in a water maze task after tryptophan treatment was attributable to high levels of KYNA and QUIN in the hippocampus acting synergistically on N-methyl-D-aspartic acid receptors. When branched-chain amino acids were administered, tryptophan transport to the extracellular space of the striatum was drastically inhibited. CONCLUSION: Our findings demonstrate that the increase in fatigue which occurs because of excessively elevated brain tryptophan can be further amplified by the use of synthetic KYNA and QUIN.
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Fatiga/metabolismo , Serotonina/metabolismo , Triptófano/metabolismo , Acetilglucosaminidasa/deficiencia , Acetilglucosaminidasa/genética , Aminoácidos de Cadena Ramificada/uso terapéutico , Análisis de Varianza , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cuerpo Estriado/ultraestructura , Modelos Animales de Enfermedad , Prueba de Esfuerzo/métodos , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Fatiga/tratamiento farmacológico , Fatiga/genética , Fatiga/fisiopatología , Femenino , Fluoxetina/farmacología , Ácido Hidroxiindolacético/metabolismo , Ácido Quinurénico/administración & dosificación , Locomoción/efectos de los fármacos , Locomoción/genética , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Microdiálisis , Ácido Quinolínico/administración & dosificación , Ratas , Ratas Mutantes , Ratas Sprague-Dawley , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Conducta Estereotipada/efectos de los fármacos , Conducta Estereotipada/fisiología , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Factores de TiempoRESUMEN
The number of synaptic AMPA receptors (AMPARs) is the major determinant of synaptic strength and is differently regulated in input pathway-dependent and target cell type-dependent manners. In cerebellar Purkinje cells (PCs), the density of synaptic AMPARs is approximately five times lower at parallel fiber (PF) synapses than at climbing fiber (CF) synapses. However, molecular mechanisms underlying this biased synaptic distribution remain unclear. As a candidate molecule, we focused on glutamate receptor δ2 (GluRδ2 or GluD2), which is known to be efficiently trafficked to and selectively expressed at PF synapses in PCs. We applied postembedding immunogold electron microscopy to GluRδ2 knock-out (KO) and control mice, and measured labeling density for GluA1-4 at three excitatory synapses in the cerebellar molecular layer. In both control and GluRδ2-KO mice, GluA1-3 were localized at PF and CF synapses in PCs, while GluA2-4 were at PF synapses in interneurons. In control mice, labeling density for each of GluA1-3 was four to six times lower at PF-PC synapses than at CF-PC synapses. In GluRδ2-KO mice, however, their labeling density displayed a three- to fivefold increase at PF synapses, but not at CF synapses, thus effectively eliminating input pathway-dependent disparity between the two PC synapses. Furthermore, we found an unexpected twofold increase in labeling density for GluA2 and GluA3, but not GluA4, at PF-interneuron synapses, where we identified low but significant expression of GluRδ2. These results suggest that GluRδ2 is involved in a common mechanism that restricts the number of synaptic AMPARs at PF synapses in PCs and molecular layer interneurons.