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Aim: Neuroinflammation is an important causal factor for a variety of psychiatric disorders. We previously reported increased cerebrospinal fluid interleukin‐6 levels in patients with schizophrenia and major depressive disorder. The present study aimed to examine the possible association of interleukin‐6 levels with anxiety and frustration, negative valence symptoms shared in various psychiatric disorders. Methods: We included 129 patients with psychiatric disorders and 70 controls. CSF and plasma interleukin‐6 levels were measured by immunoassay kits, and psychological symptoms were assessed with the State–Trait Anxiety Inventory, and the Basic Psychological Need Satisfaction and Frustration Scale. To examine regional cerebral blood flow, patients underwent arterial spin labeling analysis using magnetic resonance imaging. Results: Cerebrospinal fluid interleukin‐6 levels were significantly correlated with State–Trait Anxiety Inventory‐trait anxiety (r = 0.25, P = 0.046) and Basic Psychological Need Satisfaction and Frustration Scale‐autonomy frustration scores (r = 0.29, P = 0.018). Patients with abnormally high cerebrospinal fluid interleukin‐6 levels (defined >97.5 percentile of the controls) had higher scores for trait anxiety (P = 0.035) and autonomy frustration (P = 0.026), and significantly increased regional cerebral blood flow in the left superior temporal gyrus, bilateral nucleus accumbens, and cerebellum than the remaining patients. Conclusion: Patients with elevated cerebrospinal fluid interleukin‐6 constitute a subpopulation of psychiatric disorders associated with anxiety and autonomy frustration, which may be related to altered functions in specific brain areas. [ABSTRACT FROM AUTHOR]

Alterations in the white matter have been implicated in schizophrenia. Myelin basic protein (MBP), a component of the myelin sheath, in the cerebrospinal fluid (CSF) has been suggested as a biomarker for white matter damage in demyelinating diseases. This prompted us to examine the CSF‐MBP levels in patients with schizophrenia. We analyzed the CSF‐MBP levels in 152 patients with schizophrenia and 117 age‐ and sex‐matched controls. A significant positive correlation between age and CSF‐MBP levels was observed both in the patients (p < 0.001) and controls (p = 0.014). No significant difference was observed in the CSF‐MBP levels between the two groups. However, among a subsample of the patients (N = 32), a significantly negative correlation was observed between CSF‐MBP and age‐adjusted motor speed score of the brief assessment of cognition in schizophrenia (ρ = −0.59, p < 0.001). Further, among patients who underwent diffusional magnetic resonance imaging of the brain (N = 27), the CSF‐MBP levels showed a significantly negative correlation with the mean kurtosis value in the right temporo‐parietal region (p < 0.001). Our results suggest that the CSF‐MBP level has limited utility as a diagnostic marker; however, higher CSF‐MBP levels are associated with poorer motor speed, which may be associated with regional white matter damage in the brain in patients with schizophrenia. [ABSTRACT FROM AUTHOR]

Low‐grade neuroepithelial tumors are major causes of drug‐resistant focal epilepsy. Clinically, these tumors are defined as low‐grade epilepsy‐associated neuroepithelial tumors (LEATs). The BRAF V600E mutation is frequently observed in LEAT and linked to poor seizure outcomes. However, its molecular role in epileptogenicity remains elusive. To understand the molecular mechanism underlying the epileptogenicity in LEAT with the BRAF V600E genetic mutation (BRAF V600E‐LEAT), we conducted RNA sequencing (RNA‐seq) analysis using surgical specimens of BRAF V600E‐LEAT obtained and stored at a single institute. We obtained 21 BRAF V600E‐LEAT specimens and 4 control specimens, including 24 from Japanese patients and 1 from a patient of Central Asian origin, along with comprehensive clinical data. We submitted the transcriptome dataset of 21 BRAF V600E‐LEAT plus 4 controls, as well as detailed clinical information, to a public database. Preliminary bioinformatics analysis using this dataset identified 2134 differentially expressed genes between BRAF V600E‐LEAT and control. Additionally, gene set enrichment analysis provided novel insights into the association between estrogen response‐related pathways and the epileptogenicity of BRAF V600E‐LEAT patients. Our datasets and findings will contribute toward the understanding of the pathology of epilepsy caused by LEAT and the identification of new therapeutic targets. [ABSTRACT FROM AUTHOR]

Lewy body‐related α‐synucleinopathy (Lewy pathology) has been reported in patients with myotonic dystrophy (DM) type 1 (DM1), but no detailed report has described the prevalence and extent of its occurrence. We studied consecutive full autopsy cases of DM1 at the National Center of Neurology and Psychiatry (NCNP) Brain Bank for intractable psychiatric and neurological disorders. Thirty‐two cases, genetically determined to be DM1 (59.0 ± 8.7 years), obtained from the NCNP Brain Bank, were compared with control cases obtained from the Brain Bank for Aging Research (BBAR) in Japan. The investigated anatomical sites followed the Dementia with Lewy Bodies Consensus Guideline, expanding to the peripheral autonomic nervous system, temporal pole, and occipital cortex, in addition to the olfactory epithelium and spinal cord. Of the 32 patients, 11 (34.4%) had Lewy pathology, with a significantly higher prevalence than that in the control cases from the BBAR (20.1%). Lewy pathology detected in DM1 was widespread, but no macroscopic depigmentation of the substantia nigra was observed in any DM1 case; this was commensurate with the microscopic paucity of Lewy pathology in the substantia nigra and amygdala. Lewy pathology in DM1 does not appear to follow either Braak's ascending paradigm or the olfactory–amygdala extension. Lewy neurites and dots in DM1 were very sparse in the cerebral cortex and distinct from those observed in BBAR control cases. This study was the first demonstration of unique Lewy pathology in DM1 and may contribute to the understanding of the protein propagation hypothesis of Lewy pathology. [ABSTRACT FROM AUTHOR]

During development, neural progenitors are in proliferative and immature states; however, the molecular machinery that cooperatively controls both states remains elusive. Here, we report that cyclin D1 (CCND1) directly regulates both proliferative and immature states of cerebellar granule cell progenitors (GCPs). CCND1 not only accelerates cell cycle but also upregulates ATOH1 protein, an essential transcription factor that maintains GCPs in an immature state. In cooperation with CDK4, CCND1 directly phosphorylates S309 of ATOH1, which inhibits additional phosphorylation at S328 and consequently prevents S328 phosphorylation‐dependent ATOH1 degradation. Additionally, PROX1 downregulates Ccnd1 expression by histone deacetylation of Ccnd1 promoter in GCPs, leading to cell cycle exit and differentiation. Moreover, WNT signaling upregulates PROX1 expression in GCPs. These findings suggest that WNT‐PROX1‐CCND1‐ATOH1 signaling cascade cooperatively controls proliferative and immature states of GCPs. We revealed that the expression and phosphorylation levels of these molecules dynamically change during cerebellar development, which are suggested to determine appropriate differentiation rates from GCPs to GCs at distinct developmental stages. This study contributes to understanding the regulatory mechanism of GCPs as well as neural progenitors. SYNOPSIS: CCND1‐dependent phosphorylation and stabilization of ATOH1 in granule progenitor cells is dynamically regulated by the WNT‐PROX1 pathway during cerebellar development and determines the rate of granule cell (GC) differentiation from granule cell progenitors (GCPs). The expression of ATOH1 and NEUROD1 distinguishes two different progenitor maturation stages in the developing cerebellar external granule cell layer.CCND1/CDK4‐mediated phosphorylation of ATOH1 at Ser309 prevents its phosphorylation at Ser328 and thereby ATOH1 degradation.Increased expression of WNT and PROX1 promotes differentiation of GCPs to GCs by suppressing the expression of CCND1. [ABSTRACT FROM AUTHOR]

The molecular mechanisms underlying neurodevelopmental disorders (NDDs) remain unclear. We previously identified Down syndrome cell adhesion molecule like 1 (Dscaml1) as a responsible gene for Ihara epileptic rat (IER), a rat model for human NDDs with epilepsy. However, the relationship between NDDs and DSCAML1 in humans is still elusive. In this study, we screened databases of autism spectrum disorders (ASD), intellectual disability (ID)/developmental disorders (DD) and schizophrenia for genomic mutations in human DSCAML1. We then performed in silico analyses to estimate the potential damage to the mutated DSCAML1 proteins and chose three representative mutations (DSCAML1C729R, DSCAML1R1685* and DSCAML1K2108Nfs*37), which lacked a cysteine residue in the seventh Ig domain, the intracellular region and the C‐terminal PDZ‐binding motif, respectively. In overexpression experiments in a cell line, DSCAML1C729R lost its mature N‐glycosylation, whereas DSCAML1K2108Nfs*37 was abnormally degraded via proteasome‐dependent protein degradation. Furthermore, in primary hippocampal neurons, the ability of the wild‐type DSCAML1 to regulate the number of synapses was lost with all mutant proteins. These results provide insight into understanding the roles of the domains in the DSCAML1 protein and further suggest that these mutations cause functional changes, albeit through different mechanisms, that likely affect the pathophysiology of NDDs. [ABSTRACT FROM AUTHOR]

A proper balance between proliferation and differentiation of cerebellar granule cell precursors (GCPs) is required for appropriate cerebellar morphogenesis. The Skp1‐Cullin1‐F‐box (SCF) complex, an E3 ubiquitin ligase complex, is involved in polyubiquitination and subsequent degradation of various cell cycle regulators and transcription factors. However, it remains unknown how the SCF complex affects proliferation and differentiation of GCPs. In this study, we found that the scaffold protein Cullin1, and F‐box proteins Skp2, β‐TrCP1 and β‐TrCP2 are expressed in the external granule layer (EGL). Knockdown of these molecules in the EGL showed that Cullin1, Skp2 and β‐TrCP2 enhanced differentiation of GCPs. We also observed accumulation of cyclin‐dependent kinase inhibitor p27 in GCPs when treated with a Cullin1 inhibitor or proteasome inhibitor. Furthermore, knockdown of p27 rescued enhancement of differentiation by Cullin1 knockdown. These results suggest that the SCF complex is involved in the maintenance of the proliferative state of GCPs through p27 degradation. In addition, inhibition of Cullin1 activity also prevented cell proliferation and enhanced accumulation of p27 in Daoy cells, a cell line derived from the sonic hedgehog subtype of medulloblastoma. This suggested that excess degradation of p27 through the SCF complex causes overproliferation of medulloblastoma cells. [ABSTRACT FROM AUTHOR]

Background: AMPA receptors predominantly mediate fast excitatory synaptic transmission in the mammalian brain. Post‐translational protein S‐palmitoylation of AMPA receptor GluA subunits at their C‐termini reversibly controls the receptors trafficking to and from excitatory glutamatergic synapses. Excitatory inputs to neurons induce the expression of immediate early genes (IEGs), including Arc, with particular spatial patterns. In the hippocampal dentate gyrus, Arc is mainly expressed in the upper (dorsal) blade at the basal state. GluA1 C‐terminal palmitoylation‐deficient (GluA1C811S) mice showed enhanced seizure susceptibility and disturbed synaptic plasticity without impaired gross anatomy or basal synaptic transmission. These mutant mice also exhibited an increased expression of IEG products, c‐Fos and Arc proteins, in the hippocampus and cerebral cortex. In this report, we further analyzed excitability and Arc expression pattern in the dentate gyrus of GluA1C811S mice. Methods and Results: Electrophysiological analysis of granule neurons to measure the evoked excitatory postsynaptic current/evoked inhibitory postsynaptic current ratio revealed that excitatory/inhibitory (E/I) balance was normal in GluA1C811S mice. In contrast, immunohistochemical staining showed an abnormal distribution of Arc‐positive cells between upper and lower (ventral) blades of the dentate gyrus in these mutant mice. These data suggest that deficiency of GluA1 palmitoylation causes perturbed neuronal inputs from the entorhinal cortex to the dentate gyrus, which potentially underlies the excessive excitability in response to seizure‐inducing stimulation. Conclusion: Our findings conclude that an appropriate regulation of Arc expression in the dentate gyrus, ensured by AMPA receptor palmitoylation, may be critical for stabilizing hippocampal neural circuits and may suppress excess excitation. Compared with wild‐type mouse (top), AMPA receptor GluA1 Cys811Ser palmitoylation‐deficient mouse (bottom) shows abnormal expression pattern of immediate early gene Arc in the hippocampal dentate gyrus. An appropriate regulation of Arc expression in the dentate gyrus, ensured by AMPA receptor palmitoylation, may be critical for stabilizing hippocampal neural circuits and may suppress excess excitation. [ABSTRACT FROM AUTHOR]

The layer structure has been intensively characterized in the developing neocortex and cerebellum based on the various molecular markers. However, as to the developing dorsal midbrain, comprehensive analyses have not been intensely carried out, and thus, the name as well as the definition of each layer is not commonly shared. Here, we redefined the three layers, such as the ventricular zone, intermediate zone and marginal zone, based on various markers for proliferation and differentiation in embryonic dorsal midbrain. Biphasic Ki67 expression defines the classical VZ, in which there is clear separation of the mitotic and interphase zones. Next, we mapped the distribution of immature neurons to the defined layers, based on markers for glutamatergic and GABAergic lineage. Interestingly, Tbr2 and Neurog2 were expressed in the postmitotic neurons. We also report that active (phosphorylated) JNK is a useful marker to demarcate layers during the embryonic stage. Finally, we validated the final arrival layers of the migratory glutamatergic and GABAergic neurons. These results form a foundation for analyses of brain development, especially in the proliferation and migration of excitatory and inhibitory neurons in the dorsal midbrain. Patterns of gene expression in the VZ, IZ and MZ at E13.5 of dorsal midbrain. The VZ is subdivided into the mitotic zone (M zone) and the interphase zone (I zone). Postmitotic early neural markers expressed in the interphase zone of the VZ and IZ. [ABSTRACT FROM AUTHOR]

Abstract: Neural development is accomplished by differentiation events leading to metabolic reprogramming. Glycosphingolipid metabolism is reprogrammed during neural development with a switch from globo‐ to ganglio‐series glycosphingolipid production. Failure to execute this glycosphingolipid switch leads to neurodevelopmental disorders in humans, indicating that glycosphingolipids are key players in this process. Nevertheless, both the molecular mechanisms that control the glycosphingolipid switch and its function in neurodevelopment are poorly understood. Here, we describe a self‐contained circuit that controls glycosphingolipid reprogramming and neural differentiation. We find that globo‐series glycosphingolipids repress the epigenetic regulator of neuronal gene expression AUTS2. AUTS2 in turn binds and activates the promoter of the first and rate‐limiting ganglioside‐producing enzyme GM3 synthase, thus fostering the synthesis of gangliosides. By this mechanism, the globo–AUTS2 axis controls glycosphingolipid reprogramming and neural gene expression during neural differentiation, which involves this circuit in neurodevelopment and its defects in neuropathology. [ABSTRACT FROM AUTHOR]

In the nervous system, there are hundreds to thousands of neuronal cell types that have morphologically, physiologically, and histochemically different characteristics and this diversity may enable us to elicit higher brain function. A better understanding of the molecular machinery by which neuron subtype specification occurs is thus one of the most important issues in brain science. The dorsal hindbrain, including the cerebellum, is a good model system to study this issue because a variety of types of neurons are produced from this region. Recently developed genetic lineage-tracing methods in addition to gene-transfer technologies have clarified a fate map of neurons produced from the dorsal hindbrain and accelerated our understanding of the molecular machinery of neuronal subtype specification in the nervous system. [ABSTRACT FROM AUTHOR]

In the nervous system, there are a wide variety of neuronal cell types that have morphologically, physiologically, and histochemically different characteristics. These various types of neurons can be classified into two groups: excitatory and inhibitory neurons. The elaborate balance of the activities of the two types is very important to elicit higher brain function, because its imbalance may cause neurological disorders, such as epilepsy and hyperalgesia. In the central nervous system, inhibitory neurons are mainly represented by GABAergic ones with some exceptions such as glycinergic. Although the machinery to specify GABAergic neurons was first studied in the telencephalon, identification of key molecules, such as pancreatic transcription factor 1a (Ptf1a), as well as recently developed genetic lineage-tracing methods led to the better understanding of GABAergic specification in other brain regions, such as the spinal cord, the cerebellum, and the cochlear nucleus. [ABSTRACT FROM AUTHOR]

Abstract: The amyloid precursor protein (APP) is a key protein involved in the development of Alzheimer’s disease. We previously identified a signal transduction secretory pathway in which the small G protein Rac sets downstream of the cAMP/Epac/Rap1 signalling cascade regulating the α cleavage of APP [Maillet, M. et al. (2003) Crosstalk between Rap and Rac regulates secretion of sAPPα. Nat. Cell Biol. 5, 633–639]. We now report that Rap1 can physically and specifically associate with the guanine nucleotide exchange factor (GEF) STEF through its TSS region. A deleted TSS domain of STEF cells fails to activate Rac1 and dramatically decreases secretion of the non-amyloidogenic soluble form of APP (sAPPα) induced by the cAMP-binding protein Epac. Altogether, our data show that upon Epac activation, Rap1 recruits STEF through its TSS region and activates Rac1, which mediates APP processing. [Copyright &y& Elsevier]

The coordinated migration of neurons is a pivotal step for functional architectural formation of the mammalian brain. To elucidate its molecular mechanism, gene transfer by means of in utero electroporation was applied in the developing murine brain, revealing the crucial roles of Rac1, its activators, STEF/Tiam1, and its downstream molecule, c-Jun N-terminal kinase (JNK), in the cerebral cortex. Functional repression of these molecules resulted in inhibition of radial migration of neurons without affecting their proper differentiation. Interestingly, distinct morphological phenotypes were observed; suppression of Rac1 activity caused loss of the leading process, whereas repression of JNK activity did not, suggesting the complexity of the signaling cascade. In cultured neurons from the intermediate zone, activated JNK was detected along microtubules in the processes. Application of a JNK inhibitor caused irregular morphology and increased stable microtubules in processes, and decreased phosphorylation of microtubule associated protein 1B, raising a possibility of the involvement of JNK in controlling tubulin dynamics in migrating neurons. Our data thus provide important clues for understanding the intracellullar signaling machinery for cortical neuronal migration. [ABSTRACT FROM AUTHOR]

Activation of Rac by guanine-nucleotide exchange factors (GEFs) has been suggested to play an important role in cell migration which is critical for tumor metastasis. Here we investigated the role of P-Rex1, a novel specific GEF for Rac, in human prostate cancer cell migration. PCR and immunofiuorescent staining showed that the expression of P-Rex1 was undetectable in normal prostate epithelial cells (PrEC) and less metastatic LNCaP cells but significantly increased in more metastatic prostate cancer cell lines (DU-145, PC-3-LN4 and PC-3). Our study also revealed increased P-Rexl protein level in human prostate tumor specimens compared to the corresponding normal prostate tissues. Using an in vitro transwell migration chamber assay, we found that NIH-3T3 conditioned media (3T3-CM) can induce prostate cancer cell migration which positively correlates with expression levels of P-Rex1. Exogenously expressed P-Rex1 enhanced Gi-coupled receptor-dependent migration of PC-3-LN4 cells up to four-fold in a dose-dependent manner. Knockdown of endogenous P-Rex1 by small interfering RNA reduced the migration of PC-3 cells. Furthermore, exogenous expression of P-Rex1 in PC-3-LN4 cells induced strong Rac-dependent lamellipodia. Our results suggest that up-regulation of P-Rex1 promotes prostate cancer cell migration and contributes to the metastasis of prostate cancer. [ABSTRACT FROM AUTHOR]

Accurate mitotic division of neural stem and progenitor cells (NSPCs) is crucial for the coordinated generation of progenitors and mature neurons, which determines cortical size and structure. While mutations in the kinesin-like motor protein KIF23 gene have been recently linked to microcephaly in humans, the underlying mechanisms remain elusive. Here, we explore the pivotal role of KIF23 in embryonic cortical development. We characterize the dynamic expression of KIF23 in the cortical NSPCs of mice, ferrets, and humans during embryonic neurogenesis. Knockdown of Kif23 in mice results in precocious neurogenesis and neuronal apoptosis, attributed to an accelerated cell cycle exit, likely resulting from disrupted mitotic spindle orientation and impaired cytokinesis. Additionally, KIF23 depletion perturbs the apical surface structure of NSPCs by affecting the localization of apical junction proteins. We further demonstrate that the phenotypes induced by Kif23 knockdown are rescued by introducing wild-type human KIF23, but not by a microcephaly-associated variant. Our findings unveil a previously unexplored role of KIF23 in neural stem and progenitor cell maintenance via regulating spindle orientation and apical structure in addition to cytokinesis, shedding light on microcephaly pathogenesis. [ABSTRACT FROM AUTHOR]